Search Results

Why Speed Matters in GPCR Drug Discovery Nine out of ten GPCR programs stall  not because the target was wrong, but because teams waited too long to test the right thing. Terry has seen this story play out for 40 years — and he’s helping rewrite the ending. In accelerating GPCR drug discovery, the bottleneck isn’t target identification — it’s turning validated hits into real therapies fast. Attrition rates in early pharmacology remain painfully high. Molecules that look promising in vitro often unravel in vivo. Programs stall. Timelines stretch. But what if you could navigate these bottlenecks using the field-tested decision logic  of one of the most experienced pharmacologists alive? That’s exactly what Terry’s Corner  was built to do: bring four decades of frontline discovery insight straight to discovery-phase scientists and R&D strategists — without the noise, hype, or outdated models. In this session, you’ll gain: ✅ Proven strategies  to balance in vitro vs. in vivo testing early — when it matters most. ✅ Practical ways  to integrate kinetics, allostery, and bias into smarter development decisions. ✅ Insider guidance  on how real teams decide which GPCR programs to advance or kill. The High Cost of Pharmacology Gaps Every experienced drug hunter knows this: validation isn’t the problem anymore. Screening technologies, structure-informed design, and AI are accelerating target selection. The real friction point lies downstream : translating receptor–ligand interactions into actionable development decisions. A well-behaved molecule in a dish can fail spectacularly in vivo, leaving teams with years of sunk costs and little to show for it. Terry puts it bluntly: “Once you have a molecule, everything boils down to pharmacology—hit, lead, candidate, drug. And the rate of attrition in these steps is still atrocious.” Terry’s Corner is designed to shorten that distance between initial promise and actionable clarity. Scientists get frameworks, not guesswork. Early In Vivo Wins the Race When is the right time to move beyond cell assays? Earlier than many teams do. “The sooner you get your molecule in vivo, the sooner you know whether anything’s happening—and whether it’s the right or wrong thing,” Kenakin emphasizes. In vitro work is invaluable for mechanistic understanding—assay volume control, expression system contrasts, predictive pharmacology. But in vivo testing reveals the physiological truth . A smart program doesn’t wait until late stages to validate its assumptions. GPCR Kinetics: The Critical Data You Can’t Afford to Skip Equilibrium potency data only tells part of the story. Real systems don’t live at equilibrium. “Target residence time in vivo correlates beautifully with activity. Potency does not,” says Kenakin. High-throughput screens and static binding curves are easy to run, but ignoring kinetic profiling  means missing the factors that often make or break clinical efficacy. Modern real-time assays can deliver these insights earlier, faster, and cheaper than most teams assume. Kinetics isn’t an afterthought—it’s a competitive advantage . Allostery Is Not Optional Anymore The GPCR field is no longer a binary world of agonists and antagonists. “GPCRs are nature’s prototype allosteric proteins. Everything they do is allosteric.” Allosteric modulators and biased ligands aren’t exotic outliers—they’re increasingly common outcomes of modern screening. Teams that don’t understand how to detect, interpret, and exploit these mechanisms risk walking away from valuable compounds. Kenakin reminds us: “Allostery will seek you—even if you don’t seek it.” Antibodies, Bias, and the Expanding Modality Landscape Antibody therapeutics are now entering spaces once dominated by small molecules. Biased antibodies and allosteric antibody modulators are no longer theoretical—they exist. This expands the strategic toolbox for discovery teams: Bias isn’t an “optional property” to design in later. It shows up naturally. Allosteric antibodies can mirror or exceed small molecule complexity. Early cross-screening can flag biased phenotypes long before animal studies. How CRO Communication Impacts GPCR Drug Development Success Even the best science falters without operational precision. CRO partnerships are essential for most discovery programs, but they often break down on communication . “Scientists love to control experiments. CROs have standard ways of doing them. You must bridge that gap,” Kenakin notes. Teams that proactively define experimental nuances early avoid receiving “perfectly executed wrong assays.” Every misaligned study is not just wasted budget—it’s lost time. Program Kill vs. Advance: What Real Teams Do How do large pharma teams decide whether to advance or pause a GPCR program? It’s less bureaucratic than most outsiders think. Programs aren’t killed because of bad ideas—they’re paused when the chemical matter isn’t compelling enough or when strategic focus shifts. “In industry, scientists bring targets forward. There’s no central committee handing down orders. Grassroots science drives the agenda.” For scientists in discovery, this means two things: Technical clarity drives survival. Strategic communication drives momentum. Key Questions Answered in this AMA Session How early in vivo models sharpen go/no-go calls. Why kinetic profiling matters more than most teams realize. How to embrace (not fear) allosteric complexity. What happens inside Big Pharma when programs are paused or advanced. How better CRO communication prevents costly errors. 👉  Join Terry’s Corner & Secure Your Spot for the October 30 AMA Why Terry’s Corner Terry’s Corner  is a living, growing knowledge hub led by Terry Kenakin—a world authority in pharmacology. Here, you’ll get: Weekly lectures  that sharpen your command of how enzyme activity drives pharmacokinetics and drug design. A growing on-demand library  where enzyme inhibition, activation, and metabolism are demystified with clarity you can act on. Monthly AMAs  where you can challenge Dr. Kenakin with your own enzyme or GPCR interaction puzzles. Direct input  on future sessions—so topics match the hurdles your team faces in discovery and development. Decades of kinetic insight  reframed into actionable tools for faster, cleaner decision-making. Every molecule tells a story about how it binds, signals, and behaves. This AMA helps you read that story faster, so you don’t just generate data—you generate direction. 🟢 40 years of expertise at your fingertips:   Explore the complete library ➤ ✳️ Want to know what’s inside?   Read the latest articles ➤ Stay sharp between lectures.   Subscribe to The Kenakin Brief  today ➤

📰 GPCR Weekly News, July 29 to August 4, 2024 Hey there, readers! Take a look at our GPCR coverage for this week. We've got 11 GPCR papers, seven industry news pieces, a new GPCR event, and even a job ad.   This week's highlight includes congrats to: Miles Thompson , Alexander Hauser , Caroline Gorvin ,   et al.   for their work on GPCR gene variants and human genetic disease Ilana Kotliar , Thomas Sakmar , et al. for their study on Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins Nicholas Kapolka , Geoffrey Taghon , and Daniel Isom  for their research on Advances in yeast synthetic biology for human GPCR biology and pharmacology Dr. GPCR University Early-Bird Registration Open for Premium Members! Unlock a 25% exclusive discount on these courses with Dr. Terry Kenakin with our premium membership and enjoy a 1-month FREE trial! Don’t miss out—secure your spot today! Registrations for the public will be on Monday! Hurry! Courses Schedule and  Benefits Every Thursday at 10 am EST Online Lectures 1:1 meeting with Dr. Terry Kenakin Reading Materials Access to the private group Certificate of participation Learn the essentials: Measuring the pharmacologic activity of ligands (affinity, efficacy, co-operativity) Determining mechanisms of action for new GPCR ligands Elements of a comprehensive and effective GPCR discovery Master advanced applications: Using new cellular assays to analyze GPCR ligand behavior Predicting activity and in vivo target coverage with real-time kinetics Discovering new ligands and GPCR behaviors for unique drug profiles   GPCR Event Highlight 11th Adhesion GPCR Workshop Join us in vibrant Mexico City from October 23-25, 2024, to connect with fellow scientists and explore the latest in adhesion GPCR biology. Logo Contest : Let your creativity shine by submitting your design for the Logo Contest before August 15, 2024 Sponsorship Opportunities :   Elevate your brand's presence at this scientific event . Contact us at Hello@DrGPCR.com   to learn more. Your participation is eagerly awaited!  Let’s dive into the   Classified GPCR News  from July 29th to August 4th, 2024 GPCR Activation and Signaling ONE-GO: Direct detection of context-dependent GPCR activity Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins Molecular mechanism of bitter taste receptor agonist-mediated relaxation of airway smooth muscle GPCR Binders, Drugs, and more Expanding Structure-Activity Relationships of Human Urotensin II Peptide Analogues: A Proposed Key Role of the N-Terminal Region for Novel Urotensin II Receptor Modulators GPCRs in Oncology and Immunology G protein-coupled receptor-mediated signaling of immunomodulation in tumor progression Methods & Updates in GPCR Research GPCR Signaling: A Study of the Interplay Between Structure, Energy, and Function Engineering a GPCR-based yeast biosensor for a highly sensitive melatonin detection from fermented beverages The calcium-binding photoprotein clytin II: Expression of the preferred human codon-optimized clytin II gene in Chinese hamster ovary-K1 cells and its use in the G-protein-coupled receptor assays Predicting the Hallucinogenic Potential of Molecules Using Artificial Intelligence Reviews, GPCRs, and more G protein-coupled receptor (GPCR) gene variants and human genetic disease Advances in yeast synthetic biology for human G protein-coupled receptor biology and pharmacology Industry News Muscarinic drugs breathe new life into schizophrenia pipeline GPCR Dynamics Reveal Mechanisms for Drug Discovery DMS: Linking Protein Structure To Function AbbVie Completes Acquisition of Cerevel Therapeutics Nxera Pharma attended the Drug Discovery Ecosystem Summit Tectonic Therapeutic Announces Closing of Merger with AVROBIO as well as Concurrent Private Placement of $130.7 Million Tectonic Therapeutic Announces US IND Clearance for Lead Program, TX45   GPCR Events, Meetings, and Webinars September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry NEW October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs NEW Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Senior or Lead Researcher   Senior Scientist, Cryo-Electron Microscopy   Postdoctoral Research Associate Join Dr. GPCR Ecosystem

Watch Episode 175 From failed assays to breakthroughs in GPCR modeling , Dr. Jens Carlsson’s path into science was anything but straightforward. When he first began working in a lab, success seemed elusive: experiments often failed, and bench work felt unnatural. At one point, he even questioned whether research was the right career for him. The turning point came from an unexpected source: a letter of recommendation. A professor highlighted Carlsson’s talent in molecular modeling, a skill he hadn’t yet recognized as central to his future. That recognition shifted everything. Today, Carlsson is a Professor of Computational Biochemistry at Uppsala University and one of the most respected voices in GPCR modeling , where his group uses structure-based techniques not just to explain experimental results but to predict them.   Finding Science Through Serendipity Carlsson didn’t grow up with a vision of becoming a scientist. Raised in a small town in southern Sweden, he had never met anyone with a PhD and had little exposure to research. When he moved to Uppsala in the late 1990s to study engineering, it was biotechnology—then on the rise—that caught his interest. Inspired by news stories about breakthroughs like the cloning of Dolly the sheep and genetically modified foods, he saw life sciences as a field full of promise. Still, early research internships were rocky. A summer spent purifying proteins highlighted his discomfort at the bench. While others refined lab techniques, he found himself gravitating toward structural models in his spare time. He was naturally drawn to analyzing solved protein structures—an activity that, unbeknownst to him, was laying the groundwork for a future in computational modeling.   Discovering Modeling (and GPCRs) by Accident That interest led him to pursue a thesis at Scripps Research in San Diego, where he focused on how proteins respond to pH changes using molecular simulations. It was the first time he found himself immersed in a computational environment, and he realized how much he enjoyed the intellectual energy of modeling communities. When he returned to Sweden for his PhD, he focused on small molecule design. At the time, there were no solved structures of GPCRs readily available, so his work remained disconnected from that target class. It wasn’t until his postdoctoral years at UCSF—under Brian Shoichet—that GPCRs entered his scientific view. His introduction came through a practical suggestion: explore a new protein family that was gaining traction in the structural biology world. At that point, very few GPCR crystal structures had been determined. This scarcity made the field both exciting and high-risk. With limited structural data but a growing pharmacological interest, GPCRs presented the perfect challenge for someone who wanted to build predictive models from scratch.   Predictive GPCR-Ligand Modeling Carlsson's work quickly shifted from curiosity to impact. One of his early projects involved the A2A adenosine receptor, a GPCR with known relevance in diseases like Parkinson’s. Using virtual screening, he was able to identify novel ligands that aligned with experimental findings. This success was a revelation—it was possible not only to interpret experimental data but to forecast  it through modeling. This realization sparked a new guiding principle: computational tools should aim to predict experimental outcomes. For Carlsson, this marked a shift in how his lab approached GPCR research. Rather than focusing solely on explaining receptor behavior post hoc, his group began developing workflows and strategies that could drive experimental design forward.   Bridging Computation and Collaboration While Carlsson began his scientific career with a deep skepticism about collaborations—particularly with experimentalists—his experiences in the GPCR field forced a reevaluation. He came to see that effective GPCR research requires true interdisciplinary integration. Collaborating with chemists, biologists, and pharmacologists not only made his predictions more useful, but also shaped the kinds of questions his lab could ask. Today, his group includes around ten computational chemists and one in-house medicinal chemist. The division of labor reflects a pragmatic approach to problem-solving. While early stages of a project often rely on virtual screening from commercial compound libraries, the work inevitably reaches a point where novel, non-commercial ligands are needed. This is when the synthetic expertise of the chemist becomes essential. Pharmacology, on the other hand, is often outsourced through collaborations with expert labs who specialize in particular receptors. Carlsson notes that it’s easier to find pharmacologists to run assays than it is to persuade chemists to synthesize new compounds based on computational predictions—a sentiment that highlights the skepticism that still exists around modeling in some corners of drug discovery.   Embracing Complexity and Failure Carlsson’s approach to modeling is rooted in scientific humility. He emphasizes that not every question can be answered computationally—and that saying “we don’t know” is a valid, and often necessary, scientific position. When asked whether a compound is twice as potent as another, he’s quick to point out the limitations in both experimental and computational resolution. This perspective influences how his lab trains students. It's not enough to run simulations or generate models. Trainees must learn how to interpret assay data, understand pharmacological context, and communicate across disciplines. Many of his former students now work in industry, where their ability to bridge the computational-experimental divide makes them highly valuable.   Career Lessons for Young Scientists Carlsson’s journey holds several lessons for early-career researchers. First and foremost: follow the questions that keep you up at night. He believes genuine interest—not trends or external validation—is what sustains long-term scientific productivity. The daily failures and rejections of research require an intrinsic motivation that goes beyond job titles or metrics. He also underscores the importance of mentorship—not just for guidance, but for perspective. Good mentors help shape thinking without prescribing decisions. For Carlsson, influential mentors helped him find confidence in his own scientific voice while remaining open to other perspectives. Finally, he advises young scientists to celebrate small wins. In a field where major publications and grant awards can be rare, finding satisfaction in an optimized curve, a new insight, or a well-modeled structure is what keeps momentum going.   AI and the Future of GPCR Modeling Carlsson is excited by the potential of tools like AlphaFold  and the continued evolution of AI in structure prediction. His lab has already begun using AlphaFold models to identify ligands for targets that lack experimental structures. While these tools aren’t perfect—and sometimes fail in unexpected ways—they represent a shift in what’s possible. Still, he emphasizes that data limitations remain a major challenge, especially when it comes to small molecule prediction. Unlike protein sequences, small molecule data are often fragmented, inconsistent, or unavailable, making model training more difficult. Until better datasets emerge, predictive modeling will continue to rely on creative integration of computational and experimental insights.   Modeling a Career on Your Own Terms Carlsson’s career shows that failures can evolve into strengths and that computational insights can transform how we approach GPCRs. As predictive modeling matures, its role will continue to expand, guiding ligand discovery, informing pharmacology, and accelerating translation into the clinic. For early-career researchers, the takeaway is direct: GPCR drug discovery will increasingly depend on those who can unite modeling with experimentation, turning predictions into real therapeutic breakthroughs. Hear the full conversation with Jens Carlsson 🎧 Catch the full episode on the Dr. GPCR Podcast 💡 Stay curious. Stay connected. Looking for more insights like this? The Dr. GPCR Premium Ecosystem  gives you exclusive access to thought leaders, technical resources, and deep-dive content you won’t find anywhere else. 🔬 Fuel your science. 🤝 Grow your network. 🚀 Lead the future.

Molecular innovation This Week’s GPCR Intelligence: The next edge in discovery isn’t louder exposure—it’s smarter engagement. This week’s Dr. Kenakin from Terry's Corner shows how to tame irreversible drugs so their kinetic power works for you, not against you. You’ll get a framework to predict duration, penetration, and PK/PD separation—so decisions move faster and risks surface earlier. Breakthroughs this week:  nanomedicines targeting PAR2 for sustained analgesia; Emerging Voices in GPCR Biology; Domain Therapeutics patents new PAR2 antagonists. 🔍 This Week in Dr. GPCR Premium: Sneak Peek Industry insights:  Confo VLAIO grant; Skye CB1 Ph2 miss; Chugai CT-388 in-license; Septerna valuation. Upcoming events:  Membrane-mimetic screening; GPCR Forum 2025; GPCR-TDD Summit Europe. Career opportunities:  Sr. Scientist—In-vitro Pharm; Postdoc roles. Must-read publications:  AT1R β-arrestin bias; UII receptor structure; β2AR constant-pH dynamics. Terry's Corner – Control Target Engagement—Don’t Chase It with Irreversible Drugs When binding outlives exposure, everything changes. This feature frames how to define “irreversible” in real systems, anticipate PK/PD separation, and use target turnover to tune duration. You’ll see why tight binding can backfire on tissue penetration, where k_inact/K_I beats classic Ki, and how to quantify what matters—speed of inactivation and durability of effect. If your team is designing covalent or tight-binding candidates, these principles reduce surprises and accelerate dose optimization. You’ll avoid costly missteps by: Preventing kinetic traps —spot PK/PD decoupling early so washouts and C_max don’t mislead dosing strategy. Designing for penetration —balance on/off rates to reach inner tissue, not just peripheries. Quantifying what counts —prioritize k_inact and k_inact/K_I to compare irreversible inhibitors realistically. 🎥  Live AMA with Dr. Kenakin — October 30, 12 PM EST   Join Dr. Kenakin live and bring the questions that keep you thinking. Each AMA feeds directly into next month’s lessons—your real-world challenges shape what comes next.   Your Membership Gives You: Proven frameworks used in real discovery programs On-demand lessons built for tight research schedules A say in the topics covered next Weekly updates that keep your knowledge sharp Monthly live AMAs with Dr. Kenakin Trusted insights from biotech, pharma, and academia 🎬 Plus New: Lesson Trailers   Curious about Terry’s Corner before committing? Watch our new trailers for a preview of expert-led GPCR training designed for scientists and drug hunters.    💎  $2,999/year — the cost of one conference = a year of expert training — Premium Members Enjoy Over 50% Discount at Checkout Get Yearly Access On-Demand Now — Free 7 Day Trial ➤ DrGPCR Podcast: Jens Carlsson on Predictive Modeling Prediction over explanation—that’s the shift. Jens Carlsson shares how structure-based design, molecular dynamics, and smart collaboration turn models into decisions, with practical guardrails on AlphaFold’s limits. Ideal for scientists who want modeling to guide experiments, not just narrate them. Value at a glance: From screens to hits —how to identify novel GPCR ligands with structure-based workflows. Know the limits —where AI helps and where it still overpromises. Bridge the aisle —modelers × experimentalists for faster iteration. Listen to the episode ➤ Why Dr. GPCR Premium Membership Gives You an Edge Premium provides scientists with weekly expert lectures, industry updates, priority events, targeted roles, and editorial context, allowing proactive action before signals become headlines. It’s an operating system for discovery decisions, featuring practical frameworks, trusted curations, and a community that accelerates your progress. Staying current is essential as kinetics, structure, and signaling evolve rapidly. Premium keeps you oriented and out of avoidable dead-ends. FAQ 🔹 What’s included?   The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, and on-demand expert frameworks—plus member-only discounts. 🔹 Who is it for?   GPCR scientists, translational pharmacologists, biotech discovery teams, and decision-makers who need fast, curated, career-relevant intelligence. 🔹 Why now?   GPCR innovation is accelerating; act on the right signals today to shape tomorrow’s breakthroughs—and avoid delays others won’t see coming 👉 Already a Premium Member? Access this week’s full Premium Edition here ➤ What our members say "Thank you for bringing this course with Dr. Kenakin… sorely needed in the field." — DrGPCR University Attendee 🚀 Join now — and learn to design drugs that don’t just bind tighter, but work smarter and last longer. Become a Premium Member today. ➤ 🎓 Full GPCR University + 🔬 200+ expert talks 🗞️ Weekly research, careers & event intelligence 🤝 Members-only networking, AMAs & matchmaking 💡 Support open resources for the global GPCR field 🧠 Designed for researchers at every career stage

Watch Episode 174 You never forget the day your data surprises you—in a positive way. For Dr. Eric Trinquet, that moment arrived when his team successfully tracked GPCR internalization in native beta cells. They achieved this without complex imaging or radioactive materials. It was simply a clean, scalable assay—and a wave of new possibilities. This success was not mere luck. It was the result of chemistry, collaboration, and relentless effort until the signal finally confirmed: “We’re in.” From Bench to Breakthrough: Why pHSense Matters Decades of GPCR research have relied heavily on engineered systems. These include overexpression, tags, and fluorescent imaging. While they produce impressive data, they also impose artificial constraints. What if you could directly measure receptor internalization in physiologically relevant cells without disrupting their native state? That’s the promise of pHSense, a groundbreaking reagent developed by Eric Trinquet and his team at Revvity. This innovation emerged from years of foundational work in photophysics and GPCR pharmacology. Instead of creating another black-box assay, they designed pHSense around rare-earth europium probes. These probes shift brightness and fluorescence lifetime as pH changes. It’s a subtle yet powerful innovation. These probes become brighter and have a longer lifespan as internalized receptors enter acidic endosomes—translating biology into signal, instantly and accurately. Why does this matter? Until now, visualizing GPCR trafficking required imaging or forced overexpression. pHSense offers a high-throughput, no-wash, plate-reader-compatible assay with real-world relevance. The Chemistry That Almost Didn’t Work Designing pH-sensitive rare-earth complexes was not an obvious choice. The chemistry involved is notoriously complex. Solubility poses significant challenges. Even minor adjustments can compromise photophysical properties. However, Trinquet’s team, in collaboration with Professor David Parker from Durham University, cracked the code. They learned how to fine-tune both brightness and fluorescence lifetime. This led to the creation of a two-dimensional pH response curve capable of detecting subtle endosomal acidification. “You’re not changing the spectrum. You’re just changing how bright it is—and how long it glows,” said Dr. Eric Trinquet. Once they identified a lead compound, it became evident: this was not just another probe. This was the foundation of a new set of assay tools. The Day It Worked — Without Overexpression Trinquet describes this as a cornerstone moment. After months of adjustments, a scientist on his team presented a data set that transformed everything: a clean, dose-dependent response of GLP-1 receptor internalization in native beta cells. No imaging. No genetic modification. Just a plate reader, an agonist, and an endogenous GPCR. This achievement was not only technically impressive; it was conceptually transformative. For the first time, a team demonstrated high-throughput internalization data in physiologically relevant cells. Behind Every Probe Is a Partnership While the final product may arrive neatly packaged, the journey behind pHSense was anything but straightforward. The chemistry originated from Parker’s lab. The biological validation came from Jean-Philippe Pin’s group at the Genomic Functional Institute in Montpellier. The Revvity team acted as the glue. They constructed the platform, tested every variable—pKa, brightness, lifetime—and made decisions that few would even consider measuring. These were not mere vendor-supplier relationships. They were collaborative scientific ventures, years in the making. The outcome is not just a probe; it’s a tool scientists can trust. Mini Timeline: pHSense Development Early 2020s: Rare-earth probe synthesis begins Collaborative screening of scaffold families Key milestone: Clean signal in endogenous beta cells Revvity commercial launch Building a Scalable Platform — Not a One-Off Assay The brilliance of pHSense lies not only in the chemistry but also in its modularity. The assay is compatible with SNAP-tags, FLAG-tags, HA-tags, and even antibody fragments for native GPCRs. Whether in industry or academia, whether overexpressing or not, you can adapt the assay to your system. Since it operates on plate readers without wash steps, it is suitable for full-scale compound screening. “Don’t chase the shiny imaging tool if it doesn’t scale. Build or adopt assays that can evolve with your questions—like pHSense.” What’s Next? Follow the Feedback For Trinquet, commercialization is not the end; it’s a new beginning. User feedback will guide the development of future tags and variants. Teams are already investigating temperature effects, biased signaling, and endogenous dynamics. There is excitement about combining pHSense with other HTRF assays for multi-pathway mapping—G protein, arrestin, internalization—on the same cell line. What started as a chemistry problem has evolved into a discovery platform. “It’s like a funnel,” Trinquet explains. “You start wide with chemistry, you narrow with biology, and at the end—if you did it right—you open new doors.” To hear the full story of how pHSense came to life—and why the GLP-1 data changed everything— 🎧 Listen to the full podcast episode here ⸻ More about Revvity pHSense Reagents GPCR Reagents Revvity on Dr. GPCR   Dr. GPCR X Revvity Collaboration ⸻ Want more like this? 👉 Join the Dr. GPCR Premium Ecosystem for behind-the-scenes access to GPCR innovators, exclusive deep-dives, and practical tools to accelerate your research or career. 👥 Build connections. 🧪 Get insights. 🎧 Stay ahead.

Get ready for an expedition, GPCR explorers! Embark on another exciting exploration of the unknown realms of GPCR research. Welcome back to your weekly GPCR quest! This Week’s Highlights: Congrats to: John Teye Azietaku , our great contributor, for his article Class B1 GPCR Dimerization: Unveiling Its Role in Receptor Function and Signaling Sonja Peter , Brian Bender , Chris De Graaf for their excellent work on Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential Today, we started the Principles of Pharmacology II course! Thank you to all participants in Dr. Terry Kenakin's educational initiative this fall! Your dedication has greatly enriched the learning experience. Let’s keep fostering a collaborative environment for sharing ideas and expanding knowledge! Classified GPCR News  Let’s dive into the   Classified GPCR News from October 21st to 27th, 2024 Industry News Call for GPCR Papers Deadline: Nov 1, 2024. Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Webinars November 5 - 7, 2024 | 16th Annual PEGS Europe   November 25 - 27, 2024 | 1st Virtual GPCR Forum Conference November 26 - 28, 2024 | GPCRs-Targeted Drug Discovery Summit Europe July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs Scientist I Cell Biology - Tectonic Therapeutic Senior Scientist, GPCR Pharmacology Research Associate - Professor Graeme Milligan Postdoc in Molecular Pharmacology - The Hauser Group Postdoctoral Scholar – iPSC in cardiac and endothelial cell function Protein Biochemist/Structural Biologist Senior Scientist/Staff Scientist, Computational Chemistry Postdoc in GPCR mechanosensing   GPCR Activation and Signaling A gain of function variant in RGS18 candidate for a familial mild bleeding syndrome Fusarium graminearum Ste2 and Ste3 Receptors Undergo Peroxidase-Induced Heterodimerization when Expressed Heterologously in Saccharomyces cerevisiae The beta 2 adrenergic receptor cross-linked interactome identifies 14-3-3 proteins as regulating the availability of signaling-competent receptors GPCRs in Neuroscience Astrocyte Gi-GPCR signaling corrects compulsive-like grooming and anxiety-related behaviors in Sapap3 knockout mice Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches Altered PLCβ/IP3/Ca2+ Signaling Pathway Activated by GPRCs in Olfactory Neuronal Precursor Cells Derived from Patients Diagnosed with Schizophrenia Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease GPCRs in Oncology and Immunology Characterization, expressional and evolutionary analysis of five fish-specific CCRs (CCR4La, CCR4Lc, CCR12a1, CCR12a2, and CCR12b) in largemouth bass (Micropterus salmoides) The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells Methods & Updates in GPCR Research Generation of CRISPR/Cas9 modified human iPSC line with correction of heterozygous mutation in exon 6 of the CaSR gene Reviews, GPCRs, and more Insight into structural properties of viral G protein-coupled receptors and their role in the viral infection: IUPHAR Review 41 Structural and Molecular Insights into GPCR Function Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential Molecular Dynamics (MD) Simulations Provide Insights into the Activation Mechanisms of 5-HT2A Receptors Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations Become a Premium Member! Get your 5-day free trial TODAY!

Greetings, Pioneers of GPCR Science! Embark on this week’s thrilling updates in GPCR research, learning opportunities, and industry developments. Don’t just stay informed—immerse yourself, expand your knowledge, and become a trailblazer in the field! This Week’s Highlights: Celebrating Excellence: Wessel A. C. Burger , Arthur Christopoulos , David M. Thal , et al., for their groundbreaking work on Positive allosteric modulation of a GPCR ternary complex Unlock Your Learning: Limited Spots Available! There are only 5 spots left for our upcoming courses, so seize the chance to learn from the best in the field. 🚨 Hurry to reserve your spot for the Principles of Pharmacology I & II BUNDLE before the Early Bird Deadline on September 27 . With just one week left, becoming a premium member is all it takes to benefit from this discount! Not a premium member yet?  No worries – you can sign up for a 5-day FREE trial! Gain access to over 500 minutes of recorded classes in our  GPCR courses   taught by Drs. Terry Kenakin  and Sam Hoare ! Every Thursday at 10 AM EST: Principles of Pharmacology I Dates: October 3, 10, 17, 24 (four sessions) Topics: Pharmacologic activity measurement, mechanisms of action, and GPCR discovery strategies. Registration deadline: September 27, 2024 Principles of Pharmacology II Dates: October 31, November 7, 14, 21, December 5 (five sessions) (we skipped Thanksgiving, of course!) Topics: New cellular assays, real-time kinetics, and unique GPCR behaviors. Registration deadline: October 25, 2024 🔥 Why You Should Enroll Now: Cost-effective & Distinctive Educational Experience Affordable courses that maintain high-quality standards. Adaptable Learning Access recorded sessions at your convenience to enhance your understanding. Our Students Highly Recommend Us! Previous students praise the course content and our exceptional service. Join us for an exciting discussion with Dr. Terry Kenakin to gain insights and prepare for upcoming courses. Don't miss this valuable opportunity! Exclusive Deal for Scientists Residing and Working in Developing Nations If you live and work  in a developing country, please complete this form to enjoy complimentary access to Dr. Kenakin's upcoming courses. Our goal is to ensure that education is within reach for everyone! Secure your spot today and dive into the evolving world of GPCRs! GPCR Event Spotlight Discovery on Target’s 19th Annual GPCR-Based Drug Discovery Targeting G Protein-Coupled Receptors for New Therapeutic Options 📍  Boston, MA 📅 October 2 -3, 2024 Join leading scientists to investigate the most recent advancements in GPCR-targeted drug development, incorporating machine learning, innovative biophysical methods, and medicinal chemistry. Register today for the GPCR Drug Discovery Conference and save $200 with discount code “ DRGPCR24 ”. 11th Adhesion GPCR Workshop    📍  Mexico City 📅 October 23-25, 2024 Engage with your peers and delve into the latest developments in adhesion GPCR biology. The full agenda is now available; check it here ! If you want to enhance your brand, email Hello@DrGPCR.com  for sponsorship opportunities. Classified GPCR News  Let’s dive into the   Classified GPCR News from September 9th to 15th, 2024 Industry News MBX aims for $136M IPO to take potential rival to Ascendis' Yorvipath into phase 3 Certa Therapeutics Announces International Non-Proprietary Name for its First-in-class GPR68 Inhibitor Asengeprast (FT011) AlphaProteo generates novel proteins for biology and health research Innovate UK announced the winners of its Transforming Cancer Therapeutics grant, which focuses on developing life-changing cancer treatments. 𝗦𝘂𝗺𝗺𝗮𝗿𝘆 𝗼𝗳 𝘁𝗵𝗲 𝗿𝗲𝘀𝘂𝗹𝘁𝘀 𝗼𝗳 𝗔𝗘𝗙𝟬𝟭𝟭𝟳 𝗣𝗵𝗮𝘀𝗲 𝟮𝗯 𝗶𝗻 𝗖𝗨𝗗 Nxera Pharma’s Partner Centessa Announces Positive Interim Phase 1 Clinical Data with its Novel Orexin Receptor 2 (OX2R) Agonist, ORX750, in Acutely Sleep-Deprived Healthy Volunteers Cumulus raising $50M, spinning GPR68 small molecules into GIO New treatments being developed for schizophrenia Crinetics Pharmaceuticals Announces September 2024 Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) Call for GPCR Papers Deadline: Nov 1, 2024. Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Webinars September 5 - 6, 2024 | 4th Transatlantic ECI GPCR Symposium September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery September 22, 2024 | Biomolecular Horizons 2024 September 30 - October 3, 2024 | 22nd Discovery on Target October 2024 | Biologics US 2024   October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 17, 2024 | Unprecedented fragment-based screening using Spectral Shift for GPCRs October 23 - 25, 2024 | 11th Adhesion GPCR Workshop November 5 - 7, 2024 | 16th Annual PEGS Europe   NEW November 25 - 27, 2024 | 1st Virtual GPCR Forum Conference November 26 - 28, 2024 | GPCRs-Targeted Drug Discovery Summit Europe July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs HIGHLIGHT Research Associate - Professor Graeme Milligan HIGHLIGHT Postdoc in Molecular Pharmacology - The Hauser Group NEW Postdoctoral Scholar – iPSC in cardiac and endothelial cell function NEW Protein Biochemist/Structural Biologist Senior Scientist/Staff Scientist, Computational Chemistry Postdoc in GPCR mechanosensing   Postdoctoral Position Postdoctoral research position Adhesion GPCRs Loss of cardiomyocyte-specific Adhesion G Protein Coupled Receptor G1 (ADGRG1/GPR56) promotes pressure overload-induced heart failure GPCR Activation and Signaling Positive allosteric modulation of a GPCR ternary complex GPCR Binders, Drugs, and more Progress on the development of Class A GPCR-biased ligands GPCRs in Cardiology, Endocrinology, and Taste CRTC1 in Mc4r-expressing cells is required for peripheral metabolism and systemic energy homeostasis Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis GPCRs in Neuroscience Gain control of sensory input across polysynaptic circuitries in mouse visual cortex by a single G protein-coupled receptor type (5-HT2A) GPCRs in Oncology and Immunology The power of many: Multilevel targeting of representative chemokine and metabolite GPCRs in personalized cancer therapy GPR97 depletion aggravates imiquimod-induced psoriasis pathogenesis via amplifying IL-23/IL-17 axis signal pathway Structural and Molecular Insights into GPCR Function Exploring the constitutive activation mechanism of the class A orphan GPR20 Become a Premium Member! Get your 5-day free trial TODAY!

Pipeline Efficiency Meets Kinetic Power Imagine a drug that keeps working hours—or days—after it disappears from circulation. That’s the promise of irreversible drugs. But it’s also the reason a promising lead can turn toxic overnight. This session unpacks how persistent binding can either accelerate your program—or quietly kill it. That’s the power (and the peril) of irreversible drugs. These aren’t just “stronger binders.” They’re kinetic game-changers —compounds that rewrite the relationship between ligand , receptor , and physiologic outcome . Understanding how persistent binding affects receptor turnover, tissue penetration, and PK/PD relationships can give your team a strategic edge. In this lesson, you'll gain: ✅ Clarity on what “irreversible” really means  in kinetic and pharmacologic terms. ✅ Foresight to exploit persistent binding  without triggering long-term toxic liabilities. ✅ Decision speed to prioritize smarter leads  and avoid avoidable attrition. The Kinetic Edge You Can’t Afford to Ignore Steady state isn’t just about exposure anymore. When a compound’s off-rate is slower than its clearance, its biological effect outlives its plasma presence. This is the silent advantage of many successful drugs: they bind tightly or covalently , making target coverage durable  even as drug levels drop. For discovery teams, this means a shorter exposure can yield longer efficacy windows—opening doors to lower dosing frequency, better patient compliance, and more predictable outcomes. But it also means new liability surfaces : persistent effects can’t be simply “washed out” when things go wrong. That’s why this concept isn’t optional knowledge for drug hunters—it’s a competitive necessity. Why Tight Binding Isn’t Always Good News When a drug won’t let go, you can’t either. That’s the hidden liability beneath the kinetic edge. Irreversible binding isn’t a magic bullet. It’s a double-edged sword. When a drug outlives its exposure , toxic interactions can be just as persistent as therapeutic ones. Consider irreversible inhibition of cytochrome P450 enzymes— a red flag for regulators . Such interactions can disrupt metabolic detoxification and lead to delayed, systemic toxicity. Unlike reversible inhibitors, these can’t be dialed down with clearance. For teams advancing candidates, that means identifying kinetic red flags early, not after expensive safety studies. Good molecules can fail quietly at this stage —not because they’re weak, but because they’re too strong for their own good. The Tissue Penetration Trap Here’s a paradox: high-affinity, slow-offset compounds can undermine their own efficacy . When these drugs hit structured tissues (like solid tumors), they can get trapped at the periphery, leaving inner tissue underdosed. Antibody-drug conjugates and tumor-targeting antibodies have revealed this bottleneck firsthand. The on-rate/off-rate balance  matters: too tight, and penetration stalls; too loose, and efficacy dissipates. The best drug hunters learn to tune kinetic parameters  strategically—not just chase the highest affinity. It’s a design space , not a binary choice, and penetration is just the beginning. Even if your drug reaches its target, the effect it leaves behind rewrites the PK/PD playbook. Rethinking PK/PD Relationships With classical reversible drugs, effect and exposure walk hand in hand. With irreversible or tight-binding compounds, they decouple . This PK/PD dissociation  means: Drug exposure may end, but receptor occupancy remains. Washout experiments don’t tell the full story. Dose prediction models need kinetic nuance—not just Cmax and AUC. For teams running early-stage programs, recognizing this decoupling early can sharpen dose optimization  and de-risk clinical transitions . This is where theory collides with math. You can’t model irreversible binding with the usual tools. Quantifying the Unquantifiable You can’t describe irreversible binding with classic mass action law equilibrium constants alone. The metrics shift: k_inact  (rate of inactivation) replaces static Ki values. k_inact/KI  becomes the gold standard to compare potency between irreversible inhibitors. This reframes what it means to characterize potency. Instead of “how strong,” the better question is: “ how fast does this drug inactivate the target  and how long will it stay down?” Getting this wrong doesn’t just slow a program—it can mislead the entire development strategy . Designing Strategically with Irreversible Drug Binding in Mind When irreversible mechanisms are designed, not discovered by accident , they become strategic levers: Selective, durable tumor kill. Tunable kinetic selectivity. Dosing regimens aligned with biology, not just exposure. When they’re ignored, they become sources of silent failure : under-penetration, persistent off-target effects, or late-stage regulatory rejection. This is where seasoned drug hunters separate themselves from the pack—not just knowing the kinetics , but designing with them . 👉 Unlock Irreversible Drugs —  Only in Terry’s Corner! 🎥 Next Week's Release: The First AMA Session The first Ask-Me-Anything with Dr. Kenakin  will get released next month, featuring real questions from discovery scientists tackling enzyme kinetics, receptor bias, and assay design.  Want to join the next AMA on October 30? Join Terry’s Corner and get: Frameworks proven in real discovery programs On-demand lessons  designed for busy scientists Direct input  on future course topics Weekly new releases  — always fresh, always relevant Live monthly AMA  sessions with Dr. Kenakin Content trusted by biotech, pharma, and academia 💎 $2999/year — one conference cost = a full year of expert training Premium Dr. GPCR members save 50%+  with your Weekly News code. 👉  Join Terry’s Corner & Secure Your Spot for the October 30 AMA Why Terry’s Corner Pipeline risk isn’t just at the receptor—it’s upstream and downstream, in every enzyme your compound meets . Irreversible binding can turn enzyme interactions into make-or-break kinetic events. That’s why discovery teams turn to Terry’s Corner: to build strategies that anticipate these collisions instead of reacting to them too late. Here , you’ll get: Weekly lectures  that sharpen your command of how enzyme activity drives pharmacokinetics and drug design. A growing on-demand library  where enzyme inhibition, activation, and metabolism are demystified with clarity you can act on. Monthly AMAs  where you can challenge Dr. Kenakin with your own enzyme or GPCR interaction puzzles. Direct input  on future sessions—so topics match the hurdles your team faces in discovery and development. Decades of kinetic insight  reframed into actionable tools for faster, cleaner decision-making. Irreversible drugs expose where metabolism and binding collide. If you’re not designing with persistent enzyme interactions in mind, you’re building risk into your molecule from the start. This session helps you get ahead of that curve. 🟢 40 years of expertise at your fingertips:   Explore the complete library ➤ ✳️ Want to know what’s inside?   Read the latest articles ➤ Stay sharp between lectures.   Subscribe to The Kenakin Brief  today ➤

Celtarys Research Joins Dr. GPCR – Precision Tools for GPCR Assays Dr. GPCR and Celtarys Research have teamed up. This partnership aims to bring advanced chemical probe strategies to the forefront. The goal is to accelerate receptor-targeted discovery. They will showcase innovative conjugation methods. These methods will provide scientists with direct access to emerging tools and insights. Explore the partnership Multiplexing GPCR Discovery - Sakmar Lab’s Toolkit Goes Public The latest podcast features a discussion about a scalable GPCR-RAMP assay. It highlights its journey from one receptor to a cross-family toolkit. Hear from Drs. Tom Sakmar, Emily Lorenzen, and Ilana Kotliar about creating a multiplex system with DUET-tagged constructs. Their global resource is now helping labs decode GPCR biology at scale. Read the podcast article GPCR Publication Highlights βCGRP breaks the mold: Distinct signaling patterns reveal it’s more than just αCGRP’s twin. [Nature’s peptides return:](https://ecosystem.drgpcr.com/so/bdPSktt-s/c?w=cw8ae7XNuBdiMbjg4TeUw3rdv2qYhR4rv-bqGLmA948.eyJ1IjoiaHR0cHM6Ly9kb2kub3JnLzEwLjExMTEvYnBoLjcwMDcyIiwiciI6ImUyZGZlOTFjLTM5YzgtNDA5Yi04NTUyLWI5NjUwNGRlNzc4MyIsIm0iOiJtYWlsX2xwIiwiYyI6IjAwMDAwMDAwLTAwMDAtMDAwMC0wMDAwLTAwMDAwMDAwMDAwMCJ9 The B2D consortium revives biodiversity as a source for selective GPCR ligands. GPR45 steps up: A previously orphan receptor emerges as a powerful target for appetite and obesity control. Full Breakdown of the Latest in GPCR Research Want detailed insights? Dive into this week’s research, tools, and biotech updates all in one place. It’s exciting to see how the GPCR field is evolving. With the right tools, bold ideas, and powerful collaborations, you’re not just keeping pace. You’re actively shaping what’s next. Don't miss out on the opportunity to stay informed and inspired. Stay curious! The Dr. GPCR Team

Hello GPCR Trailblazers, This week, we’re spotlighting Celtarys Research, our newest partner, featured in a blog and podcast with CSO Dr. Maria Majellaro, highlighting their fluorescent ligand tools for live-cell GPCR assays.   After 40+ years and 250 publications, Dr. Terry Kenakin is launching a new learning space with video courses, AMAs, and practical insights . Get a sneak peek  and sign up for The Kenakin Brief—his free weekly newslette r.   On the industry side, Novo Nordisk, Septerna, and Deep Apple advance billion-dollar GPCR programs, while Eli Lilly and Nxera move forward in metabolic disease.   📚 This week’s paper highlights: GLP-1R/GIPR biased agonism enhances metabolic outcomes Ghrelin receptor flips D2 signaling without a ligand MOR-PAM shows G protein-selective bias   The insights are ready. The time you’ll save is yours. Terry’s Corner is coming soon. Dr. GPCR Updates Terry’s Corner Is Coming – Get Early Access and Updates    Terry’s Corner is launching soon with monthly courses, AMAs, and real-world pharmacology from Dr. Terry Kenakin. You can already explore the platform and subscribe to The Kenakin Brief—our new newsletter packed with sneak peeks, insights, and launch news straight to your inbox.   Explore Terry's Corner From Chemistry Lab to GPCR Partner – New Podcast with Celtarys Dr. Maria Majellaro of Celtarys shares how her team translates medicinal chemistry into practical GPCR assay tools—and how their new partnership with Dr. GPCR will help researchers move faster with custom fluorescent ligands, translational insight, and tool-enabled discovery. Introducing Celtarys - Probe Development via Conjugation Strategies   Celtarys Research's first article provides a detailed examination of conjugation strategies to develop high-performance fluorescent probes. It emphasizes scaffold selection, linker optimization, and assay compatibility to enhance target binding and signal fidelity in GPCR applications.    Read the full article GPCR Publication Highlights   GLP-1R/GIPR biased agonism enhances metabolic outcomes —with dual targeting showing synergistic glucose and weight benefits.   Constitutive ghrelin receptor activity, not dimerization or ligand binding —reverses dopamine D2 signaling in a physiologically critical circuit.   A MOR-positive allosteric modulator (BMS-986122) selectively enhances opioid signaling  through specific Gα subtypes, revealing new paths to safer analgesia. Want the full breakdown? Explore this week’s research, tools, and biotech insights in one place. The insights are ready. The time you’ll save is yours. Terry’s Corner is coming soon. Stay curious, The Dr. GPCR Team

Watch Episode 174 Most scientists are taught to aim for precision and control. But what if that mindset blocks the very breakthroughs we seek? Dr. Eric Trinquet, a veteran innovator behind functional GPCR assays like HTRF and IP-One, believes rigid thinking is the enemy of discovery. In this podcast, he lays out the mindset that helped shape products used across biotech and academia—and why play, failure, and surprise are not risks to manage, but fuel to harness. If you’re building tools or careers in GPCR science, this is your playbook. The Innovation Trap: Why Most Scientists Think Too Narrowly Eric doesn’t mince words: many junior scientists don’t give themselves permission to explore. They think too narrowly, focus too early, and equate unexpected results with failure. This mindset, he argues, suffocates innovation. He knows the cost firsthand. “You can try, try, try—and fail, fail, fail,” Eric says. But those failures are where new paths emerge, often leading to transformative tools like the IP1 assay and Tag-lite. Instead of chasing linear progress, Eric encourages young scientists to stay playful longer—embracing both strategy and serendipity. A Quote That Stuck: “Be rigorous, but not too much. Frame your strategy, then let the serendipity occur.” — Dr. Eric Trinquet Built to Fail, Built to Win: Inside the IP1 Assay Origin Story The IP-One assay didn’t emerge from a master plan. It began with an unmet need: how to track Gq-coupled GPCR activity without the mess of calcium flux or radioactive columns. Eric and his team rejected the calcium route entirely. Instead, they focused on equilibrium-based assays and zeroed in on IP1 accumulation—pioneering a clean, high-throughput alternative. The real challenge? Convincing the field it worked. It took data, yes—but also a deep partnership with GPCR legend Terry Kenakin to bridge industry credibility with pharmacological rigor. Why This Matters: IP-One helped set a new gold standard for functional GPCR assays—shifting how compounds are evaluated for efficacy and bias. The pHSense Breakthrough: Two Dimensions of Discovery pHSense wasn’t built in a vacuum—it was born from decades of groundwork in rare earth chemistry and a “what if” mentality. Originally developed as ultra-bright lanthanide probes, the team realized they could tune these molecules to become exquisitely sensitive to pH changes. The innovation? Dual control: not just brightness but fluorescence lifetime, with drastic shifts as pH drops. That opened the door to something rare in functional pharmacology: plate-based GPCR internalization tracking that rivals (and sometimes beats) imaging or flow cytometry. Mini Timeline 🎯 Early 2000s: Trinquet leads IP1 & Tag-lite development 🧪 Mid-2010s: Rare-earth scaffold work begins 🔬 2023: pHSense probes optimized for dual pH response ✅ 2024: Endogenous GLP-1 internalization shown in beta cells 🚀 2025: Revvity launches pHSense A Day That Changed Everything: The Endogenous Receptor “Aha” Eric’s second “aha” moment with pHSense came the day his team showed internalization of endogenous GLP-1 receptors in rat beta cells—with no overexpression, no imaging, and no pharmacological interference. “We did a full dose-response and saw antagonism—all in one plate-based assay. That’s the day I knew we had something no one else had.” That result wasn’t just a technical win. It validated the broader goal: giving scientists tools to study receptors in their native, unmodified state—unlocking new questions about constitutive activity, agonist-induced internalization, and cellular dynamics. 🔄 What Changed After This Data: Trinquet pushed pHSense toward rapid commercialization—pivoting it from a research probe into a full product line. From Theory to Tool: How Great Products Get Built pHSense didn’t materialize overnight. It’s the product of layered collaborations—with Durham University chemist David Parker on the probe chemistry, and with Jean-Philippe Pin’s team in Montpellier to validate biological performance. Eric is clear: real innovation requires real partnerships. It also requires months—often years—of decisions, missteps, and refinements. From probe solubility to photophysics, from tag strategies to model systems, every variable was debated, tested, and validated. For Early-Career Scientists: Don’t confuse “final product” with overnight success. The catalog number is the last step in a years-long journey filled with messy iterations. Advice for the Next Generation: Don’t Over-Rationalize So what does Eric tell young scientists who want to build breakthrough products? “Don’t over-rationalize,” he says. At early stages, breadth matters more than precision. Cast a wide net. Follow anomalies. Build theories, but be ready to toss them. It’s a mindset shaped by decades in the lab—but it’s also a warning. Product development isn’t just about science. It’s about timing, teaming, testing, and failing smarter. 🚀 Why This Matters: Whether you’re launching a tool, starting a biotech, or running an academic lab—your mindset, not just your science, will determine what gets built. Want to hear Dr. Trinquet tell the story in his own words? 🎧 Listen to the full podcast episode here ⸻ More about Revvity pHSense Reagents GPCR Reagents Revvity on Dr. GPCR   Dr. GPCR X Revvity Collaboration ⸻ Want more like this? 👉 Join the Dr. GPCR Premium Ecosystem  for behind-the-scenes access to GPCR innovators, exclusive deep-dives, and practical tools to accelerate your research or career. 👥 Build connections. 🧪 Get insights. 🎧 Stay ahead.

Enhancing scientific exploration by concentrating on understanding inhibition to advance GPCR drug discovery This Week’s GPCR Intelligence: Every drug you design will meet an enzyme before it meets its receptor. If you want your molecules to survive first contact with biology, enzyme inhibition must be part of your core playbook. This week’s feature breaks down exactly how to think about inhibitors with rigor and speed, so you can make better decisions earlier in the pipeline. Breakthroughs this week:  Potentiation of GPCR signaling by ATP and sugar monophosphates; Pharmacology 2025; Nxera Pharma earns $10m milestone from AbbVie neurological deal. 🔍 This Week in Dr. GPCR Premium: Sneak Peek Here’s a curated, high-signal preview of what Premium Members get this week—no fluff, just the intel to keep you ahead. This week —NIH’s new GPCR biosensor push, a leadership shift at Septerna, and a bold thesis on stabilizing mutated GPCRs. Plus: top tracks to watch at GPCR Forum 2025, fresh postdoc openings at the ADME/signaling interface, and concise reads on β-agonists, phospho-barcodes, and GPCR allostery. Premium gives you the full context, links, and our editorial notes—this is just the teaser. Terry's Corner – How Enzyme Inhibition Shapes Every Discovery Program Every molecule meets an enzyme before it ever meets its receptor. Whether you’re designing a ligand, optimizing ADME, or predicting PK, enzyme inhibition defines what survives to make an impact. This week’s Terry’s Corner reframes inhibition not as background theory—but as a design lens for smarter discovery. You’ll explore how catalytic control, allosteric shifts, and CYP450 behavior rewrite the rules of pharmacology. Mastering inhibition isn’t just about avoiding drug–drug interactions. It’s about turning enzymes from barriers into a strategy. You’ll discover: How four inhibition modes (competitive, noncompetitive, mixed, uncompetitive) dictate potency, efficacy, and safety. Why CYP450 allostery can make or break translation from bench to bedside. When “inhibition” becomes activation—and how that insight fuels next-gen therapeutic design. 🎥 Live AMA with Dr. Kenakin — October 30, 12 PM EST Bring your toughest pharmacology questions and join Dr. Kenakin live. Each session shapes next month’s lessons—so your challenges guide the content. Your Membership Gives You: Proven frameworks used in real discovery programs On-demand lessons built for busy scientists A voice in future course topics Fresh, weekly content that stays relevant Live monthly AMA sessions with Dr. Kenakin Trusted insights across biotech, pharma, and academia 💎 $2,999/year — one conference cost = a full year of expert training Unlock On-Demand Yearly Access Now — Premium Members Get Over 50% Discount at Checkout ➤ The Innovation Trap: Why Playing It Safe Can Kill Breakthroughs Revvity's Dr. Eric Trinquet, the scientist behind IP-One, Tag-lite, and now pHSense, challenges conventional scientific thinking in this candid post. He argues that early-career researchers often fall into the trap of over-rationalizing too soon—missing out on the unexpected twists that lead to real innovation. From failing fast to embracing serendipity, Eric shares the mindset (and messy origin stories) that shaped tools now used across biotech and academia. Whether you’re building assays or a scientific career, this is a must-read on why risk, surprise, and strategy belong together. Read the Feature ➤ Summer Days: Appetite, Suntans, and GPCR Micro-Domains Two recent papers connect ciliary signaling, opsins, and melanocortin receptors to behaviors and skin biology. This spotlight from Montana Molecular dives into how OPN3’s modulation of MCR4 in appetite circuits and MCR1 in melanocytes highlights the power of localized cAMP and ion channel coupling to reshape physiology. If you care about compartmentalized signaling and native-state biology, this is a sharp, readable tour. Zoom into the cilium.  Why micro-domains change what “global” signaling can and can’t explain. Target specificity, not just potency.  Localized cAMP and channel coupling as levers for phenotype. New tools, new questions.  Biosensors make once-invisible dynamics assayable at scale. Read the roundup ➤ Why Dr. GPCR Premium Membership Gives You an Edge Premium delivers curated, noise-free intelligence every week: expert lectures that turn theory into tools, classified industry news with editorial context, priority alerts for the events that matter, real career leads, and must-read publications decoded for action. It’s built for scientists and teams who want fewer tabs and faster decisions—one scroll that blends structure, function, and discovery. Instead of chasing fragmented feeds, you get a single, credible source that respects your time and advances your work. If your program depends on seeing around corners—enzyme liabilities, signaling bias, translational risks—Premium keeps you moving smarter, not just faster. Quick FAQ 🔹 What’s included? The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, on-demand expert frameworks, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, biotech discovery teams, and decision-makers who need fast, curated, career-relevant intelligence to stay ahead. 🔹 Why now? The pace of GPCR innovation is accelerating. Those acting on the right signals today will shape tomorrow’s breakthroughs—and avoid delays others won’t see coming. 👉 Already a Premium Member? Access this week’s full Premium Edition here ➤ What our members say "The content had enough depth to satisfy the hunger for theory while being full of practical knowledge." — DrGPCR University Attendee 🚀 Transform enzyme theory into a discovery advantage and access this week’s classified intel! Become a Premium Member today. ➤ 🎓 Full GPCR University + 🔬 200+ expert talks 🗞️ Weekly research, careers & event intelligence 🤝 Members-only networking, AMAs & matchmaking 💡 Support open resources for the global GPCR field 🧠 Designed for researchers at every career stage

Most drugs don’t fail at the receptor level—they fail before they even reach it. Enzymes decide who survives. In every lab, candidates fail not because they lack potency at a receptor, but because they stumble at an unseen step: enzyme interaction . Before your GPCR ligand ever meets its receptor, it meets the enzymes that determine whether it survives long enough to act. Recognizing, predicting, and leveraging these interactions is the essence of enzyme inhibition pharmacology —the framework that connects molecular survival to clinical success. This is a critical topic that is often overlooked: how enzymes dictate drug success. In this session, you’ll gain: ✅ A clear map of how drugs interact with enzymes before, during, and after receptor binding. ✅ A strategic understanding of competitive, noncompetitive, mixed, and uncompetitive inhibition . ✅ Practical insight into how enzyme activation and inhibition shape drug safety, efficacy, and design decisions. The Overlooked Step in Every Discovery Program So what does that mean for discovery scientists designing the next generation of GPCR ligands? Even the most elegant GPCR ligand can fail if it never reaches its receptor. That reality starts with hepatic metabolism , where enzymes such as cytochrome P450s  determine a molecule’s fate. They can metabolize, inactivate, or transform your compound, sometimes into a toxic byproduct, other times into a life-saving prodrug. This lesson reframes enzyme interaction not as background noise, but as a core pharmacological event. By visualizing enzymes as dynamic molecular partners rather than static filters, drug discovery scientists can make faster, smarter optimization decisions. The takeaway? You’re not just designing for receptor activity—you’re designing for enzyme survival. Why Enzymes Once Seemed Like Magic Before modern pharmacology, enzymes were mysterious catalysts that seemed to defy chemical logic. In this lecture, you’ll revisit the early days of discovery: when scientists thought cellular chemistry bordered on alchemy. The transition from “magic” to mechanistic understanding, championed by pioneers like A.J. Clark , laid the foundation for today’s quantitative pharmacology. That same shift in mindset (seeing enzymes as predictable, targetable, quantifiable systems ) is exactly what teams need today to accelerate pipelines. It’s not nostalgia; it’s a reminder that the biggest breakthroughs often come from re-seeing what we thought we knew. Enzyme Inhibition Pharmacology: Orthosteric vs. Allosteric Control Once you see enzymes as design partners, the next question becomes: how do we control them? Enzyme inhibition isn’t one-size-fits-all. You’ll learn to distinguish orthosteric inhibition (where a molecule directly blocks the substrate’s access) from allosteric inhibition, which alters enzyme shape and activity from a distance. Why it matters: Allosteric inhibitors often retain potency under high substrate conditions, such as ATP-rich cancer cells, where orthosteric inhibitors fail. These nuances define therapeutic potential and side-effect risk. By mastering the difference, discovery teams can anticipate resistance, tune selectivity, and design molecules that adapt to real cellular environments—not just ideal assay conditions. Cytochrome P450: Friend, Foe, and FDA Focus No enzyme class is more important—or more unpredictable—than cytochrome P450s .CYP3A4 alone handles over half of all marketed drugs. It’s notoriously allosteric. Probe-dependent. And responsible for countless drug–drug interactions. Kenakin dissects how P450s can be both protective and problematic. Their broad substrate tolerance shields us from xenobiotics. But it also creates a nightmare for clinical predictability. The same compound may appear inactive in one substrate system, then wildly active in another. This lecture challenges scientists to move beyond binary inhibition data and embrace a systems-level view—because in regulatory conversations, “Does your molecule inhibit P450?”  isn’t a checkbox; it’s a survival test. The Four Faces of Enzyme Inhibition Most scientists can name “competitive” inhibition, but in this lesson, Terry makes sure everyone understands  all four archetypes: Competitive:  Substrate and inhibitor vie for the same site. Noncompetitive:  The inhibitor binds elsewhere, shutting down catalysis regardless of substrate presence. Mixed:  A hybrid effect defined by variable affinities. Uncompetitive:  Inhibitor acts only on the enzyme–substrate complex. Each mode reshapes both potency and therapeutic window. Through stories, such as how ethanol competes with methanol in cases of poisoning, you can gain insight into how simple enzyme logic translates into lifesaving interventions. These distinctions aren’t academic—they’re the rules behind every PK/PD curve you trust. When Inhibition Becomes Activation Not all enzyme interactions are suppressive. Some drugs activate  enzymes through allosteric binding, turning a passive catalytic site into a hyper-efficient engine. Explore examples of glucokinase activators  that enhance insulin release, as well as potential SIRT1   activators  linked to longevity and metabolic resilience. Understanding activation dynamics gives discovery teams a new design frontier: instead of blocking biology, they can re-tune  it. The implications extend to neurodegeneration, metabolic disease, and regenerative pharmacology—fields where fine-tuning enzyme behavior may outperform traditional antagonism. Enzymes: The Gatekeepers of Clinical Reality From early inhibitors like aspirin  and penicillin  to modern kinase modulators, enzymes have always dictated drug destiny. Yet many discovery teams still relegate them to the “ADME” checklist, rather than the strategic design space. This lesson’s core message is clear: Every molecule is judged twice—first by its receptor, then by its enzymes.Ignoring the second gatekeeper means wasting cycles, budgets, and potentially, careers. This session equips teams to see enzyme kinetics not as background theory, but as an accelerator for smarter discovery . 👉 Unlock Enzyme Inhibition — Only in Terry’s Corner ! 🎥  Coming Soon: Live AMA with Dr. Terry Kenakin This Month’s Live AMA — October 30 at 12 PM EST Join Dr. Kenakin live for an open Q&A session designed for discovery scientists. Bring your toughest pharmacology questions — from receptor bias and assay design to enzyme kinetics — and help shape next month’s discussion topics. Your Membership Includes: Frameworks proven in real discovery programs On-demand lessons  designed for busy scientists Direct input  on future course topics Weekly new releases  — always fresh, always relevant Live monthly AMA  sessions with Dr. Kenakin Content trusted by biotech, pharma, and academia 💎 $2999/year — one conference cost = a full year of expert training Premium Dr. GPCR members save 50%+  with your Weekly News code. 👉 Join Terry’s Corner & Secure Your Spot for the October 30 AMA Why Terry’s Corner The efficiency of your pipeline doesn’t hinge on one receptor—it depends on every enzyme your compound meets along the way. That’s where Terry’s Corner  gives discovery teams an edge. Here, you’ll get: Weekly lectures  that sharpen your command of how enzyme activity drives pharmacokinetics and drug design. A growing on-demand library  where enzyme inhibition, activation, and metabolism are demystified with clarity you can act on. Monthly AMAs  where you can challenge Dr. Kenakin with your own enzyme or GPCR interaction puzzles. Direct input  on future sessions—so topics match the hurdles your team faces in discovery and development. Decades of kinetic insight  reframed into actionable tools for faster, cleaner decision-making. Pharmacology isn’t just about hitting the receptor—it’s about surviving the enzymes first. If you’re still treating metabolism as an afterthought, you’re designing risk into your pipeline. 🟢 40 years of expertise at your fingertips:   Explore the complete library ➤ ✳️ Want to know what’s inside?   Read the latest articles ➤ Stay sharp between lectures.   Subscribe to The Kenakin Brief  today ➤

Enhance your GPCR research with deeper assay insights for more effective results. This Week’s GPCR Intelligence: If you want cleaner decisions, start with the system—then the ligand. This week Terry's Corner unlocks a simple lever that separates signal from storytelling, moving programs forward with fewer surprises. Breakthroughs this week: C. elegans avoids EGCG via SRXA-7 GPCR; a bidirectional GPCR switch modulates immune signaling; a machine-learning tool predicts GPCR–ligand kinetics; and cryo-EM uncovers a new allosteric site on an orphan GPCR. 🔍 This Week in Dr. GPCR Premium: Sneak Peek A fast editorial preview of what Premium Members get in full this week — so you can scan, prioritize, and act. Inside Premium:  Key FDA moves reshaping GPCR pipelines, shifting obesity and CNS strategies, and global meetings worth bookmarking. Plus: new research on CaSR, leptin signaling, and inflammation-linked GPCRs — and curated roles in computational and membrane protein science. Premium delivers the full details, links, and expert commentary every week. Terry's Corner – Assay Volume Control in GPCR Drug Discovery This week in Terry’s Corner, you’ll learn how dialing receptor expression/coupling up or down reveals hidden partial agonism, “silent” agonism, inverse agonism, and liabilities that derail translation of your GPCR drug discovery program. This isn’t academic—it’s a pipeline filter for reality-aligned decisions. See the true  pharmacology:  Lower sensitivity to uncover partial agonism and compare relative efficacy without confounders. Catch stealth behaviors early:  Boost sensitivity to expose weak agonism in “antagonists” or PAMs—before they bite you in vivo. Design for translation:  Map sensitivity ranges to tissue contexts so your plate data predicts what happens in organisms. 🎬 Plus New: Lesson Trailers   Curious about Terry’s Corner before committing? Watch our new trailers for a preview of expert-led GPCR training designed for scientists and drug hunters.   Your membership gives you:   Proven   frameworks  for real-world GPCR drug discovery Flexible , on-demand lessons for busy scientists Influence   the curriculum with your topic suggestions Weekly new releases  to stay ahead of the science Content built for biotech, pharma & academia Live monthly AMA with Dr. Kenakin every last Thursday of the month at 12pm EST 7-day free trial to explore the corner   💎 $2999/year — one conference cost = 12 months of expert training Unlock On-Demand Yearly Access Now — Premium Members Get Over 50% Discount at Checkout ➤ Coming Next Week on the Dr. GPCR Podcast Starting next week, new episodes will drop bi-weekly on Wednesday mornings  — giving you mid-week insights that connect science and strategy. We kick off with a question that cuts deep: What if your models could actually predict the future? In this upcoming episode, Dr. Jens Carlsson  (Uppsala University) joins Yamina  to explore how computational modeling is evolving from explanation to real prediction — and why that shift could reshape GPCR drug discovery. Prediction, it turns out, is only powerful if you understand its limits. 🎧 Catch up while you wait: → Catch up on the latest episodes → Read our podcast highlights Inside Revvity’s GPCR Journey: How Decades of Discovery Shaped pHSense From HTRF to pHSense: The Long Game of GPCR Innovation Most scientists only see the final kit—the catalog number, the plate-ready reagents. But behind every “new” assay is a decade of design, failure, and rethinking. In this behind-the-scenes look, Dr. Eric Trinquet traces how a series of bold pivots—from Cisbio’s HTRF platform to IP-One and now pHSense—reshaped how GPCR biology gets measured. It’s not just a story about a probe. It’s about how Revvity turns deep science into tools that endure. Read the full story➤ Why Dr. GPCR Premium Membership Gives You an Edge Premium delivers curated, noise-free intelligence every week: expert frameworks (on-demand), classified industry updates, priority event alerts, vetted jobs, and commentary that connects dots across pharmacology, chemistry, and computation. It’s built to compress your time to clarity—so you can pick better targets, stress-test hypotheses earlier, and focus on experiments that change decisions, not just dashboards. Fast FAQ 🔹 What’s included? The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, exclusive on-demand expert lectures, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, discovery teams, and decision-makers who need fast, curated, career-relevant intelligence to stay ahead. 🔹 Why now? GPCR innovation is accelerating. Acting on the right signals today prevents tomorrow’s delays—and puts you ahead when budgets and timelines tighten. 👉 Already a Premium Member? Access this week’s full Premium Edition here ➤ What our members say "Thank you for bringing this course with Dr. Kenakin. I wish Dr. GPCR the best for the sake of promoting more educational opportunities that are sorely needed in the field." — DrGPCR University Attendee 🚀 Make better calls with better inputs. Become a Premium Member today. ➤ 🎓 Full GPCR University + 🔬 200+ expert talks 🗞️ Weekly research, careers & event intelligence 🤝 Members-only networking, AMAs & matchmaking 💡 Support open resources for the global GPCR field 🧠 Designed for researchers at every career stage

Exploring the foundational stages of scientific breakthroughs with Eric Trinquet, highlighting that true innovation begins well before laboratory experiments. Featuring logos from Dr. GPCR and Revvity. Watch Episode 174 Most scientists only see the final kit—the catalog number, the plate-ready reagents. But the reality? Every GPCR assay that makes it to market carries years of failures, late-night ideas, risky bets, and off-script breakthroughs. In this behind-the-scenes look at the making of Revity’s pHSense, Dr. Eric Trinquet shares what it really takes to bring a product to life—from sketch to shelf. If you’re in GPCR discovery or biotech R&D, this is a masterclass in turning deep science into scalable tools. From Platform to Pivot: The Birth of HTRF The journey to pHSense didn’t begin with a probe. It began with a diagnostic company rethinking its core technology. Dr. Eric Trinquet joined Cisbio in the early 2000s, working on what would become HTRF—Homogeneous Time-Resolved Fluorescence. Initially applied to biomarkers in blood, its no-wash, miniaturized design caught the attention of high-throughput screeners. But there was a pivot: the tech had untapped potential for GPCRs. Functional assays for GPCRs—especially Gq-coupled receptors—were notoriously messy. Calcium flux? Not stable. IP3 detection? Radioactive and cumbersome. Trinquet’s team asked a bolder question: could they design equilibrium-based assays for pathways no one had touched before? They didn’t just ask. They delivered. Why This Matters: The GPCR toolkit scientists use today—cAMP, IP-One, and now pHSense—didn’t evolve incrementally. It was born from radical rethinking of assay design, where platform constraints became product opportunities. Built to Fail, Built to Win: The IP One Gamble After the success of their cAMP assay, Trinquet’s team took a risky bet: develop a functional readout for Gq signaling without relying on calcium. That meant targeting inositol monophosphate (IP1), a stable downstream marker of IP3. But the path wasn’t clear. Months were spent debating assay design. IP1 isn’t naturally abundant or easy to detect. The gold standard was still radioactive tracers and purification columns. Eventually, the team landed on a design that could accumulate and detect IP1 in a 384-well format. They benchmarked it against the radioactive gold standards—and it held up. “The IP-One project was one of the riskiest things we did. But the moment we got bench-level data that aligned with our design—it became a breakthrough.” — Dr. Eric Trinquet The Real Work Starts Before the Lab What most scientists don’t see is how long a product exists as theory before it exists as a neatly packaged kit. pHSense was no different. It started not with biology—but with chemistry. Revvity and academic collaborator Prof. David Parker spent years designing rare-earth europium probes. The goal wasn’t to build a pH sensor—it was to create brighter, more stable lanthanide complexes for HTRF. But a pattern emerged: some scaffolds showed dual responsiveness to pH through lifetime and brightness modulation. That opened the door to a 2D sensor—one that responded cleanly to endosomal acidification with unmatched sensitivity. Classic pH probes failed in plate readers—too noisy, too dim. pHSense rewrote that rule, enabling high-throughput GPCR internalization assays without imaging. Internalization as a Functional Readout The insight? GPCR internalization isn’t just a trafficking readout—it’s pharmacology. Trinquet’s team designed pHSense to detect that, without microscopy. By covalently attaching the probe to FLAG-tagged receptors or using labeled antibodies, they created a plug-and-play assay format. More importantly, it worked across formats: from overexpression systems to endogenous GPCRs in native beta cells. Their “aha” moment came when they ran a dose-response with Exendin-4 on GLP-1 receptors—and saw clean, plate-based internalization curves without needing a single image. Mini Timeline: The Road to pHSense → Initial lanthanide probe design with Durham University (chemistry) → Discovery of pH-sensitive dual response (brightness + lifetime) → Application to GPCR models with Jean-Philippe Pin’s lab → Breakthrough internalization data in endogenous cells expressing GLP-1R → Commercial launch of pHSense as a plate-ready assay Real Partnerships, Not Just Sponsorships Behind every breakthrough assay is a web of collaborations that rarely make the brochure. Revnity’s partnership with Durham (chemistry) and the Institute of Functional Genomics in Montpellier (GPCR pharmacology) was not transactional. It was a scientific co-creation. Academic labs tested, challenged, and refined the tools. The result was not just a reagent—but a validated method to explore GPCR function across systems and species. And this ethos continues: every product is just the beginning of a feedback loop, where customer data feeds the next generation of design. For Early-Career Scientists: If you want to work in product R&D, learn this: real innovation happens in the tension between rigor and serendipity. You’ll fail 90% of the time. The fun is what you do with the other 10%. 🎯 From Launch to Legacy For Dr. Trinquet, commercialization isn’t the end of a project—it’s a milestone in a longer journey. It’s when you invite the community in. It’s when the tools you built in-house meet the problems no one saw coming. pHSense isn’t just a probe. It’s a strategic tool for decoding GPCR behavior in drug discovery and systems biology. It reflects decades of foundational R&D—from the fluorescent probes of Cisbio’s early days to the receptor-targeting strategies of today. And for those on the front lines of GPCR science, it’s a new lens to see what’s always been there—just below the surface. Want to hear Dr. Trinquet tell the story in his own words? 🎧 Listen to the full podcast episode here ⸻ More about Revvity pHSense Reagents GPCR Reagents Revvity on Dr. GPCR   Dr. GPCR X Revvity Collaboration ⸻ Want more like this? 👉 Join the Dr. GPCR Premium Ecosystem  for behind-the-scenes access to GPCR innovators, exclusive deep-dives, and practical tools to accelerate your research or career. 👥 Build connections. 🧪 Get insights. 🎧 Stay ahead.

Every delay in the discovery pipeline compounds into wasted years, lost opportunities, and soaring costs. For drug hunters working at the GPCR interface, the difference between a successful lead and a dead-end candidate often comes down to one overlooked factor: system sensitivity and how we control it. Assay sensitivity is like adjusting the brightness on a microscope—set it right, and hidden details jump into focus, changing the story entirely.  For GPCR drug discovery, those hidden details can determine whether a compound advances or stalls. Pharmacology isn’t only about ligands, receptors, and downstream G protein signaling—it’s also about recognizing that the assay itself holds powerful information when tuned correctly. In this course, you’ll gain: ✅ How assay volume control  alters receptor sensitivity and what that reveals about candidate drugs. ✅ Why adjusting system sensitivity  can uncover hidden efficacy, silent antagonism, or even inverse agonism. ✅ Practical insights into designing assays that mimic pathophysiology , producing data with sharper predictive power. The Hidden Lever in GPCR Research In GPCR pharmacology, the conversation often centers on ligand properties—affinity, selectivity, efficacy. But what if the assay system itself  could be leveraged as a powerful experimental variable? Assay volume control does just that. By modulating receptor expression or sensitivity, we can shift the “lens” through which drug activity is revealed. For discovery teams, this isn’t an academic exercise. It’s about revealing therapeutic liabilities before  they derail development. A drug candidate that looks promising in a high-sensitivity assay may collapse under physiological stress. Conversely, a weak signal in a baseline assay may mask an opportunity—if the system were tuned differently, hidden efficacy could be exposed. The real question: are you letting your assay system dictate the wrong story? Why System Sensitivity Matters Consider the signaling cascade: ligand binds receptor, receptor couples to G protein, G protein initiates downstream events. The quantitative strength of this cascade depends not just on the ligand, but also on the abundance and coupling efficiency of the receptor system . By reducing receptor density, researchers can transform full agonists into partial ones—allowing comparative efficacy calculations that are otherwise invisible. By increasing sensitivity, so-called “silent” antagonists reveal themselves as weak agonists. With extreme overexpression, constitutive activity emerges, exposing inverse agonism.  Think of it this way: most receptors behave like switches—they stay off until flipped. But some leak current, like a switch glowing faintly in the dark. That’s constitutive activity—and it’s what lets us see inverse agonism when we crank the system up. The ability to dial  system sensitivity up or down creates a testbed where drug behaviors that normally remain hidden can be observed in sharp relief. Questions That Make or Break a Program This session doesn’t overwhelm with technical deep-dives—it teases apart practical insights by asking: How can you distinguish between a high-affinity/low-efficacy agonist  versus a high-efficacy agonist  before entering costly development phases? What if your “silent antagonist” is actually a low-level agonist in disguise—and how will that matter in vivo? Can changing receptor density predict how your drug will behave across sensitive versus less sensitive tissues? What role does constitutive activity play in uncovering inverse agonists , and how can you exploit this phenomenon for novel therapeutic strategies? These aren’t abstract academic puzzles—they’re decision points that can make or break a program. Pipeline Payoff: Assay Sensitivity for Better Predictions For drug discovery scientists, time and predictive accuracy are the currency of success. An assay that reveals drug properties earlier in the pipeline translates directly into better prioritization, cleaner data packages, and fewer late-stage surprises. Volume control strategies turn basic receptor assays into diagnostic tools that: Differentiate compounds beyond surface-level potency. Model patient-like pathophysiological states (e.g., reduced receptor expression in heart failure). Clarify whether observed effects reflect true pharmacology or assay artifacts . Every mischaracterized compound that enters animal studies or early trials is a tax on time and resources. Adjusting assay sensitivity—whether through expression systems, chemical modulation, or engineered desensitization—provides the clarity needed to avoid these detours. From Bench Insight to Strategic Advantage Terry Kenakin’s decades of pharmacology leadership converge on one principle: pipeline advantage begins with sharper experiments . Emerging drug hunters cannot afford to test compounds in default conditions alone. Instead, they must ask how the assay itself can be tuned to better mirror the biological and clinical reality. What emerges is not just more data—it’s the right data, positioned to inform strategic decision-making. Assay volume control becomes a tool for risk management, translational prediction, and mechanistic insight. In an era of accelerated GPCR-targeting innovation, these advantages define which programs advance and which stall. Unlock Assay Volume Control Only in Terry’s Corner 🎬 Watch Course Trailers Not sure yet? Get a preview of Terry’s teaching style and see why drug hunters worldwide rely on his frameworks. Short trailers give you a front-row seat before you commit. Why Members Join: Frameworks proven in discovery programs On-demand lessons built for busy scientists Influence the curriculum with your topic suggestions Weekly new releases — always fresh, always relevant Live monthly AMA with Dr. Kenakin Content trusted by biotech, pharma & academia 💎 $2999/year — one conference cost = a full year of expert training  (Premium Dr. GPCR members save 50%+ with your Weekly News code) 👉   Explore Trailers & Join Today Why Terry’s Corner The pharmacology landscape is dynamic—ligands compete, cooperate, and reshape receptor ensembles in ways that standard models often miss. That’s where Terry’s Corner  changes the game. Here, you’ll get: Weekly lectures  that sharpen the exact tools you rely on in discovery. A growing on-demand library  of expert pharmacology lessons to revisit anytime. Monthly AMAs  where you can challenge Terry with your toughest questions. Direct input  on future topics, aligning content with your team’s real-world needs. Decades of insight distilled  into frameworks you can apply immediately. Pipeline efficiency isn’t luck—it’s literacy. If you’re still treating orthosteric and allosteric interactions as interchangeable, you’re leaving precision (and money) on the table. 🟢 40 years of expertise at your fingertips:   Explore the complete library ➤ ✳️ Want to know what’s inside?   Read the latest articles ➤ Stay sharp between lectures.   Subscribe to The Kenakin Brief  today ➤

This week’s edition links ligand mechanism to the decisions that shape affinity, efficacy, selectivity, safety, and downstream assays. Welcome to this week’s Dr. GPCR Weekly News Free Edition—your clear, credible signal in a noisy field. Each week we highlight the decisions that move GPCR projects forward—from pharmacology essentials to ligand binding site strategies, bench-ready tools, and industry momentum shaping GPCR pipelines. Read fast, apply faster, and stay ahead in GPCR drug discovery with evidence-based insights—no hype, just strategies you can use. Breakthroughs this week: New work clarifies how active-state GPCR conformations can support coupling to multiple transducers; plus obesity-drug program milestones and company pipeline updates. 🔍 This Week in Dr. GPCR Premium: Sneak Peek A fast, editorial preview of what Premium Members are reading in full this week—curated, concise, career-relevant. Industry insights:  Fresh selectivity datasets on openMe; Novo’s obesity dominance faces new challengers; integrating AI + structure + throughput to accelerate GPCR programs; key psychiatry and obesity updates and a noteworthy oncology first-in-patient milestone. Upcoming events:  Practical sessions on GPCR internalization and soluble proteins; core meetings from GPCR Forum to Biophysics; plus targeted summits for discovery teams planning 2025–2026. Career opportunities:  Roles spanning research associates to principal scientists across membrane proteins, antibody production, and ion channels. Must-read publications:  Studies on active-state GPCR ensembles and their transducer coupling, biased angiotensin receptor ligands, and circuit-selective analgesia in pain models. Terry's Corner – Orthosteric vs. Allosteric Interactions When should you push the native system—and when should you partner with it? This week in Terry's Corner, we focuse on the distinction between orthosteric and allosteric mechanisms and the impact of this choice on affinity, efficacy, safety, and downstream decision-making. If your team is arguing about “potency vs. effect size vs. duration,” this is your playbook for aligning strategy with biology and avoiding preventable rework. You’ll learn how to: Solve the override vs. finesse dilemma:  When orthosterics hijack the signal vs. when allosterics fine-tune (and why that matters for target exposure and safety). Win on kinetics, not just Kd:  Dynamic binding means “affinity” moves—design readouts and decisions that respect receptor state lifecycles. Separate effect size from time:  Use allosteric modulators to expand therapeutic index and reduce overdose risk without sacrificing meaningful efficacy. 🎬 Plus New: Lesson Trailers   Curious about Terry’s Corner before committing? Watch our new trailers for a preview of expert-led GPCR training designed for scientists and drug hunters.   Your membership gives you:   📚 Proven frameworks for real-world discovery 🌍 Flexible, on-demand lessons for busy scientists 💡 Influence the curriculum with your topic suggestions 🆕 Weekly new releases to stay ahead of the science 🧠 Content built for biotech, pharma & academia 💬 Live monthly AMA with Dr. Kenakin     💎 $2999/year — one conference cost = 12 months of expert training  Premium Dr. GPCR members save  50%+  (check your Weekly News code).   👉 Explore Trailers & Join Today Inside Revvity's R&D: How pHSense Was Born The day your data surprises you—in the best possible way—is the day you know you’re onto something. For Dr. Eric Trinquet and his team at Revvity, that moment came when they watched GPCRs internalize in native beta cells—without engineered tags, radioactive tracers, or complex imaging setups. Instead, the signal came clean, scalable, and unmistakably real. It wasn’t luck. It was persistence. Years of chemistry, photophysics, and pharmacology condensed into one breakthrough: pHSense , a reagent designed to make receptor trafficking visible in the systems that matter most. From Bench Frustrations to Breakthrough Design For decades, GPCR trafficking research relied on overexpression and fluorescent imaging—powerful, yes, but far from physiological. The Revvity team asked a harder question: What if you could measure receptor internalization in native cells, without distorting biology? The answer was anything but straightforward. Rare-earth europium complexes offered potential—but the chemistry was brutal. Solubility issues, fragile photophysical properties, endless false starts. That’s where collaboration came in. Working closely with Professor David Parker of Durham University, Trinquet’s group cracked the scaffold. By carefully tuning both brightness and fluorescence lifetime, they engineered a two-dimensional pH response: probes that get brighter and glow longer as receptors descend into acidic endosomes. “You’re not changing the spectrum,” Trinquet explains. “You’re changing how bright it is—and how long it glows.” That subtle distinction opened the door to a brand-new assay format. Why It Matters Instead of imaging-heavy workflows, pHSense offers a no-wash, plate-reader–ready, high-throughput assay  that finally connects internalization readouts with physiological relevance. Available in four formats, it turns a notoriously tricky measurement into something discovery teams can actually scale—without sacrificing biological fidelity. And perhaps that’s the deeper story: Revvity’s R&D team didn’t just invent another tool. They translated a fundamental principle of chemistry into a usable platform for pharmacology—showing how persistence, precision, and the courage to take on “impossible” chemistry can shift the entire GPCR toolkit. 👉 Go behind the scenes with Revvity’s R&D team ➤ Celtarys Research – Advantages of Fluorescent Ligands in CNS GPCR Drug Discovery In neuroscience drug discovery, the right tool  can be just as critical as the right target . For GPCRs, fluorescent ligands have quietly become one of the most versatile technologies—supporting everything from hit validation to pre-clinical assays. Why? Because they give researchers something rare in CNS work: clarity in complexity. The Advantages Live-cell imaging:  visualize receptor–ligand interactions in real time, without disturbing native cell states. Subtype specificity:  selectively track receptor subtypes in complex brain tissue. Cleaner data:  higher signal-to-noise ratios sharpen CNS assays. Speed:  faster GPCR target validation and assay development. Safety:  a non-radioactive alternative, sidestepping regulatory hurdles. Why It Matters In the CNS, where receptor localization and real-time signaling shape therapeutic outcomes, fluorescent ligands deliver both precision and adaptability. B y integrating them into GPCR workflows, discovery teams can accelerate identification, characterization, and lead optimization—reducing noise while increasing confidence in every step. 👉 See how fluorescent ligands sharpen CNS drug discovery ➤ Why Dr. GPCR Premium Membership Gives You an Edge Premium provides weekly curated intelligence, including expert lectures, classified industry news, priority event alerts, focused job leads, and insider commentary. It's designed to help GPCR scientists and teams move faster by consolidating scattered updates into a single actionable stream. From assay choices to investment-grade context, you’ll see the signal early, cut delays, and make cleaner portfolio decisions while supporting open resources for the global GPCR field. FAQ: Premium Membership 🔹 What’s included? The complete Weekly News digest, curated jobs, key upcoming events, classified GPCR publications, on-demand expert frameworks, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, biotech discovery teams, and decision-makers who need fast, curated, career-relevant intelligence to stay ahead. 🔹 Why now? The pace of GPCR innovation is accelerating. Acting on the right signals today shapes tomorrow’s breakthroughs—and avoids slowdowns others won’t see coming. 👉 Already a Premium Member? Access this week’s full Premium Edition here ➤ What our members say "This came at just the most perfect time… it’s just like being at a conference getting new ideas. I couldn’t be happier you created this podcast." — DrGPCR Podcast Listener Upgrade to Premium and turn weekly noise into clear, decisive action. Your team’s next good decision may start here 🚀 Join Premium Today & Enjoy ➤ 🎓 Full GPCR University + 🔬 200+ expert talks 🗞️ Weekly research, careers & event intelligence 🤝 Members-only networking, AMAs & matchmaking 💡 Support open resources for the global GPCR field 🧠 Designed for researchers at every career stage

Every R&D team is under the same pressure: deliver validated targets, clean pharmacology, and translatable in vivo results—faster. But here’s the truth: too many programs still fail because early decisions were built on shaky mechanistic ground. The cost? Months of wasted resources, failed translation, and opportunity loss. The difference between orthosteric vs. allosteric mechanisms isn’t just academic — an orthosteric antagonist can hijack receptor physiology, while an allosteric modulator works with the system. That choice determines whether you risk over- or under-dosing, miss safety windows, or miss therapeutic breakthroughs. In this session, you’ll gain: ✅Clarity on Definitions:  What truly distinguishes orthosteric from allosteric interactions. ✅ Insight into Consequences:  How binding sites determine receptor state shifts, signaling outcomes, and efficacy profiles. ✅ Practical Perspective:  Why this knowledge reshapes dose–response interpretation and informs your pipeline’s next decision gate. Why Orthosteric vs. Allosteric Interactions Still Matter Orthosteric and allosteric interactions have been in pharmacology textbooks for decades, but today they’re strategic levers. Orthosteric ligands preempt  natural signaling; they “take over” receptor behavior, forcing physiology to follow their lead. That can be powerful but blunt. Allosterics , in contrast, act more like tuning knobs—modulating receptor ensembles in partnership with the system’s ongoing signaling. This means they can be more selective, avoid pathway saturation, and preserve physiological nuance. For drug discovery teams navigating safety margins, biased signaling, and combination therapy design, understanding which approach you’re taking is mission-critical. In this lesson, you’ll learn why this distinction is not just theory, but a practical framework to design cleaner, smarter pharmacology. The Dynamic Nature of Receptor Binding Forget the static “lock-and-key” metaphor. Ligands bounce in and out of receptor sites, competing dynamically. Orthosteric sites are zero-sum: highest affinity or concentration wins. Allosteric sites operate differently: ligands bind elsewhere, transmit energy changes, and shift the receptor ensemble’s state without direct competition. Dr. Kenakin walks through this as a living system , showing how GPCRs exist in multiple conformations and how your ligand’s presence reshapes the ensemble. This has immediate implications for interpreting EC50 shifts, partial agonism, and assay readouts—especially in systems with constitutive activity. How Conformational Changes Drive Affinity and Efficacy A key takeaway from this session: affinity and efficacy are not independent variables—they’re thermodynamically linked. A high-affinity ligand often has higher efficacy, but the relationship is not linear. By stabilizing certain receptor states over others, ligands literally remodel the energy landscape. For teams building structure–activity relationships (SAR), this insight is gold: you’re not just chasing Ki or EC50 values—you’re sculpting state probabilities. That perspective helps explain why two compounds with similar affinities can deliver very different clinical profiles. Why Allosteric Modulators Expand Your Toolkit Allosterics offer a broader range of effects—additive, synergistic, or even inhibitory—depending on cooperativity (α, β) with endogenous agonists. Unlike orthosterics, they can discriminate between agonists, pathways, and even durations of action. This means you can design molecules that potentiate beneficial pathways without shutting down basal signaling entirely, or conversely, selectively dampen overactive pathways without full receptor blockade. The result? More nuanced control, fewer off-target liabilities, and novel therapeutic windows. The Mechanistic Edge Behind Smarter Drug Discovery One of the most powerful aspects of this session is how it reframes the questions you ask of your own data. Instead of treating binding as a binary event, Terry shows you how to interrogate whether your compound acts orthosterically, allosterically, or with mixed mechanisms—and why that matters for interpreting EC₅₀ shifts and constitutive activity. You’ll learn to recognize when an inverse agonist is resetting a receptor’s set point, when a partial agonist is competing with endogenous tone, and when an allosteric modulator is adding to or potentiating the natural response. The result is not just cleaner assay design but a sharper decision framework for selecting, prioritizing, and dosing your lead series. Translational Relevance: From Bench to Clinic Misjudging orthosteric vs allosteric behavior can derail dose selection, lead to false negatives in early screens, or even mask toxicities. Correctly distinguishing these mechanisms helps refine therapeutic index calculations, prioritize safer leads, and avoid late-stage surprises. In drug discovery, orthosteric vs. allosteric isn’t just a mechanistic detail; it’s a decision that shapes your pipeline’s success. Recognizing how your ligand interacts with the receptor lets you predict safety margins, dose–response behavior, and translational risk before they derail development. Equip your team with this literacy now to design cleaner pharmacology and accelerate smarter, safer programs. Unlock Orthosteric vs. Allosteric Interactions Only in Terry’s Corner 🎬 Plus New: Lesson Trailers   Curious about Terry’s Corner before committing? Watch our new trailers for a preview of expert-led GPCR training designed for scientists and drug hunters.   Your membership gives you:   📚 Proven frameworks for real-world discovery 🌍 Flexible, on-demand lessons for busy scientists 💡 Influence the curriculum with your topic suggestions 🆕 Weekly new releases to stay ahead of the science 🧠 Content built for biotech, pharma & academia 💬 Live monthly AMA with Dr. Kenakin     💎 $2999/year — one conference cost = 12 months of expert training  Premium Dr. GPCR members save  50%+  (check your Weekly News code).   👉 Explore Trailers & Join Today Why Terry’s Corner The reality is dynamic—ligands compete, cooperate, and reshape receptor ensembles in ways that standard models miss. That’s where Terry’s Corner changes the game. Here, you’ll get: Weekly lectures  that sharpen the tools you actually use in discovery A growing on-demand library  of expert pharmacology lessons you can revisit anytime Monthly AMAs  where you can ask Terry your toughest questions Direct input  on future topics, so the content tracks your team’s challenges Decades of insight distilled  into frameworks you can apply immediately Pipeline efficiency isn’t luck—it’s literacy. If your team is still treating orthosteric and allosteric interactions as interchangeable, you’re leaving precision (and money) on the table. 🟢 40 years of expertise at your fingertips:   Explore the complete library ➤ ✳️ Want to know what’s inside?   Read the latest articles ➤ Stay sharp between lectures.   Subscribe to The Kenakin Brief  today ➤

What is Homogeneous Time-Resolved Fluorescence (HTRF)? HTRF is a hybrid detection technology that combines Förster Resonance Energy Transfer (FRET) with a time-resolved measurement . FRET is a distance-dependant energy transfer between a donor and an acceptor fluorophore, and in HTRF a delay is introduced between the time of excitation of the donor and the readout of the acceptor’s emission. The donors used in this technique have longer half-lives  than other fluorophores (between 300μs–1 ms) and can be combined with the same acceptor fluorophores used in regular FRET assays. Terbium, a second-generation donor, is brighter than Europium (10-20 times), which increases sensitivity. When the distance between donor and acceptor is close enough, energy is transferred, and a second, short-lived emission is recorded. Measuring emission at both donor (usually 620nm) and acceptor (typically 665nm) wavelengths allows for data correction , reducing variability. Figure 1. Principle of time-resolved detection. Source: Nørskov-Lauritsen L, Thomsen AR, Bräuner-Osborne H. G protein-coupled receptor signaling analysis using homogenous time-resolved Förster resonance energy transfer (HTRF®) technology. Int J Mol Sci. 2014 Feb 13;15(2):2554-72. The delay introduced in HTRF between excitation and emission detection lets the background signals dissipate , reducing the impact of background interference (from autofluorescence or light scattering). This makes it an ideal candidate for GPCR research, where accuracy in detecting subtle signaling changes is essential. Homogeneous Time-Resolved Fluorescence Assays: Overcoming Common Challenges Balancing sensitivity and scalability  is one of the hardest challenges in high-throughput screening (HTS). Traditional methods like radioligand binding assays or calcium flux measurements have significant drawbacks in this context: one is limited by radioactivity-related safety and environmental concerns, while the other one has high background noise and low dynamic range. How are these challenges overcome by HTRF? No washing. Use of 384 or 1536-well plates and compatibility with automated platforms. Signal interferences are kept to a minimum thanks to the timing of detection. The ratiometric readouts correct many inconsistencies such as pipetting errors. The donor lanthanum fluorophores are more stable than regular fluorophores and quite resistant to photobleaching. The donors act as light-harvesting antennas, capturing light from all directions, unlike the dipole-dipole alignment needed in FRET. Enhancing HTRF Assay Performance in GPCR Research Using Fluorescent Ligands GPCRs are involved in numerous physiological processes, making them a key target in drug development.  They activate several signaling pathways, via G proteins, β-arrestins, receptor tyrosine kinases, making them a complex task to study. GPCRs are not always the most numerous in cells. Quite often, there is a need to amplify the signal  strength to detect them, which can be achieved by using fluorescent ligands. This is moreso the case when detecting partial agonism or weak receptor interactions. This technology enhances sensitivity and assay specificity . By using two labeled ligands the transference of energy event will only happen when the adequate distance is achieved. This means that even if one of the ligands they are bound to is promiscuous, it will not compromise assay integrity the same way it would in single-label approaches. This is especially useful in GPCRs, where structural similarity happens often and thus cross-reactivity of ligands is common. In HTRF the lanthanide-based donors with longer emission enhance signal-to-noise ratio and red uce background interference . They can be combined with second generation acceptors like d2, as well as brighter donors, further increasing sensitivity and assay specificity. This also improves detection of low affinity or slow binding ligands. On top of that, smaller acceptors like d2 reduce steric hindrance, making them more efficient. It can also be combined with  multiplexing . By using donor-acceptor pairs with different emission spectra that don’t overlap, researchers can design assays that track multiple pathways at the same time. Terbium is compatible with both red and green acceptors. This has been done in assays tracking IP1 and cAMP to detect biased agonism in GPCR ligands Table 1. Examples of HTRF donor/acceptor pairs Expanding Time-Resolved Fluorescence Applications in Drug Discovery Beyond Traditional Methods At Celtarys, we have expertise in time-resolved fluorescence applications. In a recent study , we contributed to the development of a robust HTRF assay for the discovery of new modulators for cannabinoid receptors. This assay utilized our fluorescent ligand, CELT-335 , designed for hCB 1 /CB 2  cannabinoid receptors, demonstrating high specificity and sensitivity in detecting ligand-receptor interactions.  Figure 2. Saturation assays using CELT-335. Specific binding is shown, obtained from total binding and unspecific binding (a) CB1R expressing adherent HEK-293T cells and unspecific binding measurement (specific binding measured using CP55490 at 10 μM concentration ) (b) CB 2 R expressing adherent HEK-293T cells and unspecific binding measurement (specific binding measured using GW405833  at 10 μM concentration). Data represent the mean ± SEM (n = 3 in triplicate). Source: Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M. A Robust and Efficient FRET-Based Assay for Cannabinoid Receptor Ligands Discovery. Molecules. 2023 Dec 15;28(24):8107.   Celtarys enhances the power of HTRF and other FRET-based technologies by providing high-performance fluorescent ligands designed specifically for pharmacological research. By combining deep expertise in GPCR biology with advanced fluorescence chemistry, Celtarys custom-developed ligands offer both high affinity and exceptional selectivity across a wide range of GPCR targets. References Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M. A Robust and Efficient FRET-Based Assay for Cannabinoid Receptor Ligands Discovery. Molecules. 2023 Dec 15;28(24):8107. doi: 10.3390/molecules28248107 Nørskov-Lauritsen L, Thomsen AR, Bräuner-Osborne H. G protein-coupled receptor signaling analysis using homogenous time-resolved Förster resonance energy transfer (HTRF®) technology. Int J Mol Sci. 2014 Feb 13;15(2):2554-72. doi: 10.3390/ijms15022554. Degorce F, Card A, Soh S, Trinquet E, Knapik GP, Xie B. HTRF: A technology tailored for drug discovery - a review of theoretical aspects and recent applications. Curr Chem Genomics. 2009 May 28;3:22-32. doi: 10.2174/1875397300903010022.

The blood-brain-barrier (BBB) and the complexity of the central nervous system (CNS) pose a challenge for developing successful therapeutics , particularly for neurological disorder and neurodegenerative diseases. This includes diseases such as depression, Parkinson’s, schizophrenia, and Alzheimer’s. GPCRs play a central role in neuronal signaling and have been used to treat these diseases with varying degrees of success. They mediate the effects of neurotransmitters and neuromodulators. The central role of GPCRs in Neurological Disorders GPCRs are the largest family of membrane receptors and participate in several CNS functions. Most of these are essential processes, such as neurotransmission, synaptic plasticity, mood, cognition, motor control and sensory perception. Thus, they also participate in numerous diseases. Over 30% of FDA-approved drugs target GPCRs, with many targeting CNS located GPCRs. Most of them are small molecules capable of going through the BBB , and since their targets are on the membrane of cells, they have easier access to the receptors than those that need to get into the cells to modulate intracellular signaling. One of the biggest hurdles is the understanding and correct targeting of the different receptor subtypes involved in each disease and the downstream and side effects attached to them. GPCR Structure, Activation, and Signaling Pathways in the Brain An understanding of GPCR structure is key in drug design. GPCRs posses a seven-transmembrane domain architecture, which lets them transduce extracellular signals into intracellular responses. They manage this by interacting with G-proteins. What happens when a GPCR is activated? When the endogenous binder of the GPCR (which can be a neuromodulator, neurotransmitter, etc.), binds to the extracellular binding site of the GPCR, the protein changes into its active conformation , which starts the intracellular signaling cascade. Depending on the type of GPCR, it can lead to different secondary messengers , like cAMP, IP3, which will ultimately modify gene expression, neurotransmitter release and plasticity. Figure 1. GPCR signaling: (A) an orthosteric ligand (orange) binds an inactive GPCR, the β2 adrenergic receptor (β2AR; PDB ID: 2RH1); (B) A ligand-bound GPCR undergoes a conformational change to its active state (PDB ID: 3SN6); and (C) an active GPCR binds a G protein (PDB ID: 3SN6), which subsequently promotes nucleotide release from, and activation of, the G protein α-subunit. Source: Latorraca NR, Venkatakrishnan AJ, Dror RO. GPCR Dynamics: Structures in Motion. Chem Rev. 2017 Jan 11;117(1):139-155. The activation of these pathways regulates pain modulation, memory consolidation, motor coordination etc. The concept of biased agonism must also be highlighted here. The conformation change induced by the agonist may not always lead to the same intracellular signaling . Some agonists induce conformations more adept at activating β-arrestins for example, leading to different intracellular effects. Studying these routes may reduce side-effects when using GPCR-based therapies. Emerging GPCR Therapeutic Targets in CNS Drug Discovery GPCRs have been studied for decades, but there are some, known as orphan GPCRs , which seem to be implicated in CNS pathologies but are not fully studied. Some of these are GPR6, GPR37 and GPR139 , which participate in motor control, neuroprotection and metabolic regulation. Their physiological ligands are not fully understood, which opens new treatment possibilities. GPR6 has been linked to neuroprotective functions and is now being investigated for its role in Parkinson’s disease and neuropathic pain. GPR37 has been linked to the Parkinson’s disease as well, though more focused on the progression of the disease. GPR139 is implicated in schizophrenia and ADHD. Figure 2. Orphan GPCRs related to neurodegenerative disorders. Source: Kim J, Choi C. Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches. Curr Issues Mol Biol. 2024 Oct 19;46(10):11646-11664. Of the traditional GPCRs, CBRs are gaining ground as potential therapeutic targets in several CNS diseases, such as Parkinson’s. As mentioned in previous posts, CELT-335, one of our fluorescent compounds, was successfully employed in a binding assay for CB1R and CB2R. More research into the endocannabinoid system (ECS) will let us access these GPCRs in a safer manner. Both orphan and well-characterized GPCRs are untapped opportunities for drug development targeting CNS diseases , especially as traditional targets seem to have stagnated when not focusing on biased-agonism. The newer generations of targets and screening tools will pave the way for safer and more efficient drugs. Advantages of Fluorescent Ligands in GPCR Drug Screening for CNS Choosing the right tools is important for the success of drug discovery, just as much as choosing the right targets. One of the best tools to study therapeutic targets are fluorescent ligands , which are very useful in GPCR drug discovery, starting from hit and lead validation all the way to pre-clinical assays. Some of the advantages of using fluorescent ligands for this are: Live-cell imaging:  receptor-ligand interactions can be visualized in real-time without fixating the cells. Greater specificity : allows for selective tracking of receptor subtypes in complex brain tissues. Reduced background noise: Improvements in signal-to-noise ratio are key in CNS assays. Faster assay development: also speeds GPCR target validation. Avoid safety concerns and regulatory hurdles: Non-radioactive alternative to screening In the context of CNS drug development, where receptor localization and real-time signaling are crucial , fluorescent ligands offer a powerful and adaptable solution. Their integration into drug discovery neuroscience workflows helps accelerate GPCR target identification, characterization, and lead optimization. References Latorraca NR, Venkatakrishnan AJ, Dror RO. GPCR Dynamics: Structures in Motion . Chem Rev. 2017 Jan 11;117(1):139-155. doi: 10.1021/acs.chemrev.6b00177 Alavi MS, Shamsizadeh A, Azhdari-Zarmehri H, Roohbakhsh A. Orphan G protein-coupled receptors: The role in CNS disorders . Biomed Pharmacother. 2018 Feb;98:222-232. doi: 10.1016/j.biopha.2017.12.056 Azam S, Haque ME, Jakaria M, Jo SH, Kim IS, Choi DK. G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits . Cells. 2020 Feb 23;9(2):506. doi: 10.3390/cells9020506   Kim J, Choi C. Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches. Curr Issues Mol Biol. 2024 Oct 19;46(10):11646-11664. doi: 10.3390/cimb46100691   Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M. A Robust and Efficient FRET-Based Assay for Cannabinoid Receptor Ligands Discovery. Molecules. 2023 Dec 15;28(24):8107. doi: 10.3390/molecules28248107

Innovative design approach emphasizing scientific principles over speculation. This Week’s GPCR Intelligence: From Set-Point Pharmacology to No-Wash Internalization Assays This week’s Dr. GPCR News delivers a toolkit of practical innovations—from drug design strategies that anticipate physiological resistance, to no-wash internalization detection tools, to HTRF ligand optimization techniques that reduce background noise and amplify weak signals. Whether you’re optimizing screening campaigns or navigating translational challenges, these insights give you a sharper edge. Premium Members rely on this intelligence weekly—and here’s your curated preview. Breakthroughs this week: Lilly to build $5B manufacturing facility in Virginia; Novo Nordisk flags drug trial promise; Nanobody sensor reveals β-arrestin conformational diversity. 🔍 This Week in Dr. GPCR Premium: Sneak Peek Want the full classified brief? Here’s what Premium Members accessed this week  across four critical domains: Industry insights:  Neurocrine at Morgan Stanley; Crinetics September inducement grants; fresh GPCR Q3 earnings forecasts; IIT Kanpur’s live-cell GPCR sensor. Upcoming events:  47th Symposium on Hormones & Cell Regulation; new approach to GPCR internalization analysis; “Soluble Proteins in Focus” for Cryo-EM prep; GPCR Forum Meeting 2025. Career opportunities:  Senior Scientist, Phage Display | Manager, CMC Management | Translational R&D openings Must-read publications:  New findings on structure-encoded location-biased signaling, GPCR signaling in metabolism, and future directions in biased ligand pharmacology. Terry's Corner – Designing Drugs That Anticipate Physiological Pushback Most GPCR programs don’t fail because the assay was flawed—but because in vivo counterregulation  neutralized the response. This week’s Terry’s Corner  exposes the unseen physiological “opponents” your molecule faces—and how to design around them. Avoid compensatory misreads:  Renin inhibition drops BP in normals, but not in heart failure—because cardiac output offsets the signal. Design smarter inotropes:  Dobutamine’s α-activity harnesses baroreflexes to increase contractility without runaway HR. Target protected agonism:  Internalized MT2 signaling escapes AGRP antagonism—unlike α-MSH. Unlock On-Demand Yearly Access Now — Premium Members Get Over 50% Discount at Checkout ➤ Revvity x Dr. GPCR: A Mission-Aligned Partnership That Advances the Field At Dr. GPCR , our mission is simple but urgent: Accelerate GPCR biology and drug discovery by connecting scientists with the knowledge, tools, and people that move the field forward. That’s why we partner with innovators like Revvity , whose new reagent family— pHSense™ —isn’t just another product. It’s a response to unmet scientific needs: Replace microscopy-heavy workflows with no-wash, live-cell TRF detection Empower high-throughput internalization studies, even at endogenous expression levels Offered in four flexible formats  that meet scientists where they are—Anti-FLAG, Anti-IgG, and SNAP-tag included This isn’t theoretical. As Dr. Eric Trinquet shares in a special Dr. GPCR Podcast, the Revvity team built pHSense™ from the ground up by listening to what GPCR scientists actually need—and validating it where it counts. 🎧 Go behind the scenes with Revvity —from the chemistry to the critical moments that changed everything. 👉 Discover the pHSense™ Reagents + Listen to the podcast ➤ Celtarys Research – Optimizing HTRF with Fluorescent Ligands Traditional ligand-binding approaches risk false positives and poor sensitivity—especially with weak or partial GPCR interactions. A new contributor article from our friends at Celtrays Research outlines how dual-labeled fluorescent ligands  solve this. Dual-label specificity blocks promiscuous ligand confusion Lanthanide donors + d2 acceptors = high SNR, low background Multiplex-compatible (e.g., IP1 + cAMP) for tracking biased agonism Read the full technical guide ➤ Why Dr. GPCR Premium Membership Gives You an Edge Premium delivers curated, noise-free intelligence every week:  deep-dive expert lectures, classified industry news, priority event alerts, job opportunities, and insider commentary—designed to help you move faster, smarter. No spam. No filler. Just the signals that move science. FAQ: Premium Membership 🔹 What’s included? The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, on-demand expert frameworks, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, biotech discovery teams, and decision-makers who need fast, curated, career-relevant intelligence to stay ahead. 🔹 Why now? GPCR innovation is accelerating. Those acting on the right signals today will shape tomorrow’s breakthroughs—and avoid delays others won’t see coming. 👉 Already a Premium Member? Access this week’s full Premium Edition here ➤ What our members say "I am a convert! I will keep Dr. GPCR and the offered resources in my work sphere." — DrGPCR University Attendee GPCR innovation doesn’t wait. Neither should you. Join Premium for access to expert tools, translational strategy, classified updates, and curated jobs—trusted by scientists, teams, and biotech decision-makers. 🚀 Join Premium Today & Enjoy ➤ 🎓 Full GPCR University + 🔬 200+ expert talks 🗞️ Weekly research, careers & event intelligence 🤝 Members-only networking, AMAs & matchmaking 💡 Support open resources for the global GPCR field 🧠 Designed for researchers at every career stage

Drug pipelines live and die by your ability to make fast, accurate calls. One wrong assumption about how your molecule behaves in a living system can sink months of work and millions in development costs. The real challenge? GPCR signaling almost never follows a straight path. Reflex arcs, compensatory pathways, and receptor trafficking can turn your expected outcome on its head, sometimes after you’ve already committed to a clinical strategy. This session gives you the tools to anticipate those twists before they hit your program. This article is about one big idea: GPCRs don’t act in isolation—they respond to the system they’re in, often through opposing processes that you must model to get reproducible results. In this session, you’ll gain: ✅ A mental model you can trust  for predicting how GPCR ligands behave in real physiology—not just in a dish. ✅ A pattern-recognition toolkit  to spot red flags early and make course corrections before trials derail. ✅ Practical strategies  for using receptor trafficking data and system set-points to design cleaner, more predictive experiments. Why Pipeline Efficiency Starts with Physiology Drug discovery doesn’t happen in a vacuum. Every ligand you design enters a system that is already balancing opposing forces—vasoconstriction vs. vasodilation, sympathetic vs. parasympathetic tone, signal activation vs. receptor downregulation. Ignore these forces, and your “selective” agonist may deliver surprises the first time it meets a patient. This lecture challenges the habit of treating in vitro data as destiny. Instead, you’ll walk through cardiovascular reflexes, surface signaling vs. internalization, and constitutive receptor activity to show how the body bends your molecule’s effect. If your job is to move molecules confidently toward the clinic, this is a blueprint for building a more reliable evidence base—one that accounts for biology’s counterpunch. When In Vitro Lies: The Patient vs. Volunteer Gap Many programs die in Phase II, not because the molecule is “bad,” but because its profile in patients was never truly understood. A renin inhibitor that lowers blood pressure in healthy volunteers might not drop blood pressure at all in heart failure patients, because increased cardiac output cancels the expected effect. You’ll understand why this is good news, not bad data, and how it can actually prevent harmful reflex tachycardia. The bigger lesson? Context matters. This section outlines the logic required to match preclinical models to patient physiology and avoid being misled by early screens. Once you see how patient physiology flips expected outcomes, the next step is to ask, could these reflexes work in your favor? Reflexes as Drug Design Partners Not all reflexes are enemies. Some can make a mediocre drug shine. Dobutamine’s dual action on beta and alpha receptors, for example, invites reflex bradycardia that blunts its heart rate liability—making it a better inotrope than isoproterenol in heart failure. Learn how to view reflexes not just as confounders but as potential allies. The teaser question How could you design your next lead to recruit the body’s own feedback loops in your favor? Surface vs. Internalized Signaling: Same Receptor, Different Story A GPCR response isn’t always over when the receptor leaves the membrane. In this module, you’ll explore how some receptor–agonist complexes continue signaling from endosomes, creating “protected” signaling that extracellular antagonists can’t block. This insight has huge implications for how you select and rank agonists in discovery campaigns. You’ll come away asking Which of my ligands might be producing hidden signaling from inside the cell—and how can I measure it before it surprises me downstream? System-Dependent Activity and Opposing Processes Partial agonists don’t wear single labels. The same compound can look like an activator in one system and a blocker in another—depending on basal tone. Terry illustrates this with classic β-receptor partial agonists, showing how heart rate set-points under different anesthetics can flip observed pharmacology. The takeaway? When you evaluate partial agonists, enzyme inhibitors, or antagonists, you must recreate the “working system” they’ll face in vivo—otherwise you risk throwing out molecules that would have worked. Constitutive Activity: When Doing Nothing Still Does Something Some GPCRs simply refuse to stay quiet. Ghrelin receptors, for example, signal spontaneously, meaning a neutral antagonist won’t suppress appetite; it just blocks added stimulation. Get a sense of why inverse agonists may be necessary to truly shift the physiological balance. This section raises a critical design question for teams Are you sure your “antagonist” is enough—or do you need an inverse agonist to get the clinical outcome you want? Your molecule isn’t failing—your model might be too simple. Terry’s Corner exists to fix that blind spot. Subscribe today and get direct access to decades of pharmacology experience that turn complex systems into better decisions. Why Terry’s Corner Most pharmacology training freezes at equilibrium snapshots. But drug discovery isn’t static — it’s a moving target. Ligands come and go, feedback loops kick in, and what you see in vitro rarely tells the whole story. Go inside the real-world playbook. Here’s what you’ll get: Weekly expert sessions  that turn messy data into clear decisions On-demand access  to a growing library of system-level case studies Unfiltered Q&A recordings  where challenging problems get solved live Direct input opportunities  so future sessions answer your  questions Battle-tested insight  from four decades of drug discovery experience If you’re serious about derisking your pipeline, this is where you sharpen the tools that actually move molecules forward. See beyond the equilibrium. Make decisions with confidence. 🟢 40 years of expertise at your fingertips: Explore the complete library ➤ ✳️ Want to know what’s inside? Read the latest articles ➤ Stay sharp between lectures. Subscribe to The Kenakin Brief today ➤

Discover how Revvity’s pHSense™ reagents enable real-time GPCR internalization detection A breakthrough GPCR internalization assay now featured in the Dr. GPCR Ecosystem Boston, MA – September 2025  — Dr. GPCR , the global nonprofit platform dedicated to advancing GPCR science through education, community, and platform visibility , is proud to spotlight pHSense™ , a new reagent family from Revvity , now featured across the Dr. GPCR Ecosystem. Developed to address long-standing challenges in GPCR internalization assays , pHSense™ reagents  combine live-cell, no-wash protocols  with time-resolved fluorescence (TRF) detection , enabling real-time detection of GPCR internalization —without microscopy. “The day we saw dose-dependent internalization in endogenous GLP1R cells—without microscopy—that was the turning point,” said Dr. Eric Trinquet, Director of Research and Development at Revvity.   A GPCR Internalization Tool Designed for Real Research Needs Built on more than two decade A GPCR Internalization Tool Designed for Real Research Needs s of GPCR assay innovation , pHSense™  was developed to overcome three persistent barriers in internalization studies : Complex imaging workflows Limited scalability for high-throughput screening Low sensitivity in detecting endogenous GPCRs With pHSense™, scientists can finally track GPCR internalization  in real time—even at physiological expression levels —using a simple plate-based format . The reagents are compatible with HTRF readers  and validated in GLP1R  and Mu opioid receptor (MOR)  models. Part of a Complete GPCR Reagent Portfolio pHSense™ is the latest addition to Revvity’s GPCR reagent portfolio , which supports every stage of the signaling cascade: GPCR ligand binding  – TR-FRET, radioligand, Tag-lite® G-protein activation  – cAMP, IP-One, GTP assays β-arrestin recruitment assays Downstream readouts  – phospho-ERK, AKT, CREB, MEK and other phoshoproteins These reagents are optimized for high-throughput GPCR screening , reproducibility, and translational depth. 👉 Explore Revvity’s Full GPCR Reagent Catalog 🎙️ Hear More About pHSense™ on the Dr. GPCR Podcast To mark the spotlight, Dr. GPCR  invited Dr. Eric Trinquet  to the Dr. GPCR Podcast , where he shares the story behind pHSense , including its application in real-time internalization assays  and the scientific “aha” moments that drove its development. “This isn’t just another product,” said Dr. Yamina Berchiche, Founder of Dr. GPCR. “It’s a leap forward in how the community studies GPCRs at scale and in context.” 🔗 About Dr. GPCR Dr. GPCR  is a global nonprofit platform advancing GPCR research  through education, community, and platform visibility. Through our podcast, training programs, and partner content, we help scientists connect, collaborate, and innovate in the world of G protein-coupled receptors . 🔗 About Revvity Revvity  is a global life sciences company delivering translational tools and diagnostics. Its GPCR research tools  support discovery teams and academic labs with precision reagents and validated assay platforms. 🔍 Learn More → Listen to the Podcast with Revvity’s Eric Trinquet → Explore the pHSense™ Reagent Line → Browse Revvity’s GPCR Assay Portfolio

Exploring the Hidden Dynamics: How Kinetics Reveals What Equilibrium Conceals in GPCR Research. Hi GPCR Community, If equilibrium curves are your comfort zone, this week’s feature will challenge (and strengthen) your decisions. We’re zeroing in on kinetic tools that reveal what steady-state data can’t—so you can vet leads faster, avoid false positives, and move with confidence. That’s precisely what Terry’s Corner delivers each week: practical frameworks from Dr. Terry Kenakin to elevate your science and sharpen your calls. Breakthroughs this week:  Septerna begins first-in-human trial of SEP-631 for CSU; Maxion’s KnotBody® platform; a new angle on RGS protein modulation. 🔍 This Week in Dr. GPCR Premium: Sneak Peek Here’s a fast, high-level preview of what Premium Members are unpacking this week. It’s a curated lens—just enough signal to guide your week, with the full depth available inside. Industry insights:  Orforglipron’s trajectory is redefining weight-management and diabetes markets—implications for GPCR-linked pathways and competitive positioning. Upcoming events:   Preview of Discovery on Target 2025 (Boston, Sept 24‑25), including GPCR‑Track breakout sessions; panel opportunities to engage with biophysics and structural biology leaders. Career opportunities:  Snapshot of roles spanning PhD entry points to senior translational pharmacology—Protein Expression, Drug Discovery Scientist, and Staff Scientist in Molecular Pharmacology—curated with notes on fit, skill spikes, and timelines. Must-read publications:  From on stabilizing RGS2 via modulating its degradation (versus direct inhibition); selectivity frameworks for β₂ vs β₁ adrenergic receptors tp structural insights into cholesterol interactions in the active conformation of GLP‑1 receptor Terry's Corner – Advanced Applications of GPCR Kinetics for Real-World Decision Making Equilibrium looks tidy. But kinetics tells the truth. This week, you will learn how to confirm equilibrium the right way, detect time-dependent occupancy and complex activity, leverage hemi-equilibrium calcium assays, recognize fractal potency, and surface liabilities early—before they cost you cycles and credibility. These are the pattern-recognition tools that convert uncertainty into decisions you can defend at a project review. Avoid expensive mirages:  Spot when “good” equilibrium curves mask time-dependent binding that will fail in translational settings. Protect your screening funnel:  Use hemi-equilibrium readouts to flag artifacts before they inflate your SAR. Out-decide your competition:  Apply fractal potency insights to prioritize leads that stay robust across conditions. Premium Members get a 50%+ discount when they join Terry’s Corner. 🚨 Live AMA with Dr. Kenakin is today, September 18th, 12-1 pm EST in Terry’s Corner. Corner members get to rewatch the recording Subscribe to the Kenakin Brief and Join the Live AMA ➤ Celtarys Research – Flow Cytometry Reimagined: Fluorescent Ligands vs Antibodies for Live‑Cell GPCR Studies Traditional antibody staining for GPCRs has well‑known limitations—fixation artifacts, epitope masking, low expression, conformation changes.  Fluorescent small-molecule ligands flip the script: direct binding to functional sites, live-cell compatibility, and higher specificity enable real-time tracking of interactions, internalization, and biased signaling—without fixation or permeabilization. Learn how to choose fluorophores (brightness, stability, spectra), reduce background (far-red/near-IR), and match channels to your cytometer for clean, multiparametric data. Eliminate fix/perm distortions:  Preserve receptor conformation and downstream signaling integrity. Get functional—not just presence—readouts:  Quantify affinity and kinetics where it matters. Scale confidently:  Use bright, stable ligands for HTS and bias profiling. See the full guide and example ligands ➤ Discovery on Target 2025 Speaker Spotlight: Solubilization, Orphans & Lipid Systems In a conversation with Alison Heick Varghese and Kris Borzilleri (Pfizer), we dig into detergent-free, lipid-mimic systems for reliable GPCR screening; orphan GPCR strategies; and advances across nanodiscs, peptidiscs, SMALPs, SPR, ITC—plus how construct design and solubilization choices shape success. In Boston, Sept 24–25? We’ve got your GPCR Track, Happy Hour, and sessions mapped so you can extract maximum value. Register now and save with code SPK200 ➤ Why Dr. GPCR Premium Membership Gives You an Edge Premium delivers curated, noise-free intelligence every week: expert frameworks  (like Terry’s Corner), classified industry news , priority event alerts , targeted job leads , and editorial guidance  that turns information into action. It’s built for the GPCR community—by people who live the science—so you spend less time sifting and more time deciding. If you need to brief leadership, plan experiments, or time a move in the market or your career, Premium makes sure you’re working from the clearest signal available. FAQ: Premium Membership 🔹 What’s included? The complete Weekly News digest, curated jobs and upcoming events, must-read GPCR publications, exclusive on-demand expert frameworks, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, biotech discovery teams, and decision-makers who need fast, curated, career-relevant intelligence to stay ahead. 🔹 Why now? GPCR innovation is accelerating. Those acting on the right signals today will shape tomorrow’s breakthroughs—and avoid delays others won’t see coming. 👉 Don’t Fall Behind—Access the Edge You Need 👉 Already a Premium Member? Access this week’s full Premium Edition here ➤ What our members say "Dr. Kenakin is a leading expert in the field. Aside from his vast experience in drug development, not to mention his extensive publication record, Dr. Kenakin is a masterful teacher and communicator." — DrGPCR University Attendee Everything you need to master GPCR science — in one membership. 🎓 Full GPCR University + 🔬 200+ expert talks 🗞️ Weekly research, careers & event intelligence 🤝 Members-only networking, AMAs & matchmaking 💡 Support open resources for the global GPCR field 🧠 Designed for researchers at every career stage Don’t just keep up — lead the way 🚀 Join Premium Today ➤

Join Dr. GPCR and global experts at the GPCR Drug Discovery session during Discovery on Target 2025—where groundbreaking collaborations begin. GPCR Drug Discovery at Discovery on Target 2025 — The Track You Can’t Miss If you work in drug discovery  or biotech , this is your moment. Mark your calendar, it's happening September 22-25, 2025. From obesity and diabetes to cancer, fibrosis, and CNS disorders — GPCRs  are at the heart of the world’s most pressing therapeutic challenges. And at this year’s Discovery on Target  meeting in Boston, the GPCR Drug Discovery track will deliver breakthroughs, bold ideas, and the strategies shaping the next wave of medicines . I’m honored to be chairing a session  in this track — with none other than Terry Kenakin  on the speaker lineup. 🌟 Speaker Spotlight In the run-up to the conference, our founder Yamina Berchiche is speaking with some of the brilliant minds presenting in the GPCR track. Here’s who we've talked to so far: 🎥 Check out the interview with Dr. Aaron McGrath from Takeda   🎥 Interview with Kris Borzilleri & Alison Heick Varghese from Pfizer 🎥 Interview with Terry Kenakin from UNC and Terry's Corner We'll continue to update this section as new videos are released — so check back before the meeting for fresh insights and behind-the-scenes perspectives from our speakers. 🌐 Why Dr. GPCR Is in This Conversation At Dr. GPCR , our mission is simple: connect the GPCR community, share knowledge, and accelerate innovation . At Yamina's Corner , our founder Yamina Berchiche works closely with organizations to help them navigate receptor pharmacology, identify opportunities, and move their programs forward effectively. Over the years, we’ve built a global network of researchers, biotech leaders, and pharma innovators who believe that GPCR science is one of the most powerful tools we have to address urgent health challenges. Chairing this session isn’t just another speaking engagement — it’s an extension of what we do every day: Spotlight innovation  across academia and industry. Foster collaboration  through our platform and events. Push the boundaries  of receptor pharmacology and its real-world applications. When we step into the GPCR track at Discovery on Target, we’re not just participating. We’re helping shape the conversation. 🚀 Why GPCRs Are Still the Hottest Target Class in Drug Discovery GPCRs regulate countless physiological processes, making them a goldmine for therapeutic breakthroughs. They’re already behind blockbuster drugs: GLP-1 receptor agonists  – reshaping obesity & type 2 diabetes care. CCR5 antagonists  – fighting HIV and certain cancers. Dopamine D2 receptor modulators  – transforming treatment for Parkinson’s & schizophrenia. PAR1 antagonists  – protecting cardiovascular health. But the real  excitement is in what’s next: Biased signaling  for selective therapeutic effects. Allosteric modulation  for unprecedented precision. Structure-based design  powered by cryo-EM and AI. 🔬 Inside the GPCR Track Agenda Expect deep dives into: CXCR4  in oncology and immune regulation. GIPR/GLP-1R co-agonists  in metabolic diseases. Serotonin & dopamine receptor modulation  for neuropsychiatric disorders. Orphan GPCRs  with untapped therapeutic potential. These sessions bridge structural biology , computational modeling , and clinical translation  — with tangible takeaways for programs from discovery through late-stage development. 🗝️  Highlight: Terry Kenakin at Discovery on Target Terry Kenakin’s work on functional selectivity  has transformed GPCR drug discovery, showing how to bias receptor signaling toward beneficial outcomes and away from side effects. Hearing Terry speak is more than an academic experience — it’s like being handed a new set of tools to rethink your drug design strategy. Having him in the session I’m chairing is not just an honor — it’s a highlight of the year.   📚 Terry’s Corner — The Only On-Demand Pharmacology Hub with Dr. Kenakin Himself If you’re part of the Dr. GPCR  community, you already know about Terry’s Corner  — our exclusive, on-demand pharmacology series where Terry Kenakin breaks down receptor pharmacology, functional selectivity, and ligand bias in a way you can apply directly to your work. It’s the only  resource of its kind — part masterclass, part fireside chat — available anytime to our members. For those who can’t get enough of Terry’s insights at Discovery on Target, Terry’s Corner  keeps the learning going long after the conference ends. 💡 Why This Matters — Even If You’re Not a GPCR Scientist GPCR pathways intersect with oncology, CNS, metabolic, cardiovascular, immunology, and fibrosis research . Whether you’re in early discovery or clinical development, the strategies here could open doors in your own therapeutic area. 🧭  Join Us in Boston 🗓 Discovery on Target  — Boston, MA 📅 September 23-25, 2025 🎯 Track:   GPCR Drug Discovery Let’s connect. Let’s debate. Let’s move GPCR drug discovery forward — together. 🚨 Mark your calendar for the GPCR Happy Hour Join us at GPCR Happy Hour , where scientists, biotech leaders, CRO professionals, and investors from around the globe meet Boston’s vibrant life sciences hub. ✨ Spark collaborations. ✨ Strengthen the GPCR community. ✨ Be part of Dr. GPCR’s nonprofit mission to connect and empower the global GPCR ecosystem. 📅 September 24, 2025 📍 Pressed Café, Huntington Ave, Boston ⏰ 6–8 PM EST ⚠️ Space is limited — Secure your spot now

If you’ve ever trusted a Ki value without asking how  it was measured, you’ve already stepped into the trap. In drug discovery, equilibrium constants look tidy. But biology isn’t tidy. Onset and offset rates (not just “final numbers”) decide which drugs succeed in patients and which ones die in development. Affinity snapshots alone won’t save your pipeline. Kinetics will. This session gives you precisely that. By the end, you’ll know how to confirm true equilibria, detect hidden drug activities, and separate safe candidates from toxic ones long before clinic. No more blind spots, only decisions rooted in reality. In this session, you'll gain: ✅ Tools to confirm true equilibrium and avoid potency errors from premature reads ✅ Methods to detect hidden mechanisms—mixtures, dual effects, or time-dependent inhibition—through curve shapes and kinetics ✅ A framework to classify antagonists and rank compounds by offset rate, using rapid calcium assays Potency Is a Ratio of Rates Two ligands compete for the same receptor. Which wins? Not just the one with higher affinity, but the one that gets there faster and leaves slower. Think of it like catching a train: two passengers have tickets (affinity), but only the one who sprints to the platform on time (fast onset) and stays seated (slow offset) actually gets the ride. Ignore this, and you’ll misrank compounds. Respect it, and you’ll see why drugs with identical Ki values diverge in vivo. This is the first trap: assuming equilibrium when you haven’t reached it.  Curves that “look fine” may hide non-equilibrated systems. The fix? Use curve shapes as diagnostics: flattened, biphasic, or lagging responses aren’t noise. They’re telling you to wait. When Equilibrium Lies Sometimes, numbers don’t add up. You calculate an equilibrium value that requires a physically impossible onset rate. That’s your signal: kinetics are moving faster than your tools can measure. It’s like calculating a runner’s pace and realizing they’d have to break the sound barrier to make the numbers work. The math itself is your clue that something else is happening. This is the second trap: trusting impossible math. If you ignore it, you risk false certainty. If you detect it, you gain texture that equilibrium constants alone can’t provide. And this texture matters; kinetics have separated safe dopamine antagonists from those with extrapyramidal side effects. Hidden Mixtures, Hidden Risks Peptides degrade. Drugs carry dual mechanisms. At equilibrium, these effects cancel. But kinetics unmasks them. Instead of clean monophasic curves, you’ll see biphasic signatures or sequential shifts—first cholinesterase inhibition, then receptor blockade. This is the third trap: assuming one mechanism when two are in play. Catch it early, and you avoid wasting months chasing the wrong SAR. The Hemi-Equilibrium Problem Calcium assays look simple. But if your antagonist has a slow offset, you’ll see depressed maximal responses that equilibrium theory can’t explain. This is the fourth trap: classifying antagonists as weak when they’re just slow. Flip it around, and you’ve got a shortcut: use depression of max in calcium assays to rapidly rank offset rates, and predict in vivo coverage before you ever dose an animal. Fractal Potency: The Illusion of Nothing, Then Everything Measure too soon, and low concentrations look inert. Suddenly, at higher doses, you see an exaggerated ‘bang’ of effect. It’s like waiting for popcorn: at first, nothing happens, then suddenly the bag explodes with pops. But that’s timing, not a different kind of corn. That’s not pharmacology. That’s kinetics. This is the fifth trap: misclassifying your antagonist because you didn’t wait. The cure is simple: extend equilibration. Once you do, the irregular potency vanishes, and the true profile emerges. What You’ll Walk Away With By the end of this session, you won’t just “know about kinetics.” You’ll know how to use  kinetics to sharpen decisions: Confirm whether your system has truly equilibrated Detect hidden activities before they waste resources Classify antagonists by offset rate without waiting on PK data Spot time-dependent inhibition that signals toxic liabilities Avoid being fooled by fractal potency artifacts This isn’t academic nuance. It’s the difference between building a solid pipeline and chasing ghosts. Kinetics in Drug Discovery: Your Edge If you’re still treating potency as a static number, you’re missing half the story. Kinetics turns confusion into clarity, reveals risks earlier, and helps you rank compounds by the criteria that matter most in patients. This isn’t just another lecture. It’s a shift in how expert drug hunters see pharmacology. And once you see it, you’ll never go back. Unlock “Kinetics: Advanced Applications” Only in Terry’s Corner Why Terry’s Corner Most pharmacology training stops at equilibrium values. But discovery doesn’t. The reality is dynamic—ligands arrive, depart, and interact in ways that standard assays often miss. That’s where Terry’s Corner changes the game. Here, you’ll find: Weekly lectures  that sharpen the tools you actually use in discovery A growing on-demand library  of lessons you can revisit whenever you need them Exclusive access  to the next AMA session Direct engagement opportunities  through AMAs and topic suggestions Practical insights  distilled from decades of pharmacology experience Whether you’re validating assays, refining kinetic models, or deciding which leads to advance, Terry’s Corner gives you the frameworks to detect hidden liabilities and uncover real drug potential. See beyond the equilibrium. Make decisions with confidence. 🟢 40 years of expertise at your fingertips: Explore the complete library ➤ ✳️ Want to know what’s inside? Read the latest articles ➤ Stay sharp between lectures. Subscribe to The Kenakin Brief  today ➤

Fluorescent probes illuminate the mysteries of GPCRs in cutting-edge research. Hi GPCR Community, If you work on GPCR discovery, you already know: early signals can mislead, and timing your next decision is career-critical. This week, we focus on how to convert ambiguous data into confident, defensible Mechanism of Action calls—before resources drift. That’s precisely what Terry’s Corner delivers every week: practical tools from Dr. Terry Kenakin to elevate your science and sharpen your decisions. Breakthroughs this week:  5-MeO-DMT: the "God Molecule"; Novo Nordisk looks to next generation of obesity, diabetes drugs with $550M Replicate research deal; Rhythm Pharmaceuticals Announces FDA Acceptance of sNDA for Setmelanotide in Acquired Hypothalamic Obesity. 🔍 This Week in Dr. GPCR Premium: Sneak Peek A fast, editorial preview—enough to guide your attention, not replace your due diligence. Industry insights:  Biopharma returns to MC4R; Recursion completes Exscientia acquisition, signaling a fresh AI–GPCR chapter; OMass–Genentech deal in IBD. Upcoming events:  “Drug Discovery at Superluminal Speeds”; and Discovery on Target 2025—GPCR track you’ll want on the calendar. Career opportunities:  Research Assistant; Postdoctoral Associate; Senior Scientist, Data Science—curated roles aligned to GPCR discovery and translational pharmacology. Must-read publications:  β-arrestin2-biased allosteric modulator for pain beyond opioids & GPR3 regulated by a negative allosteric modulator Terry's Corner – Determine GPCR MoA Early (and Right) Early discovery often serves you overlapping curves and noisy baselines; different mechanisms can masquerade as the same “effect.” This week’s Terry’s Corner lesson shows how to replace inference with models that disentangle mechanism—so your next go/no-go, dose range, and assay design are anchored in prediction, not intuition. You’ll apply a model-first workflow to classify orthosteric vs. allosteric behavior, stress-test assumptions through fit→predict→test loops, and improve SAR by separating affinity from efficacy. What you’ll gain—immediately relevant to your pipeline: Stop costly misreads:  Distinguish orthosteric vs. allosteric effects by extending predictions, not eyeballing plots—so you don’t advance a “hit” that collapses in validation. Engineer assays on purpose:  Set ranges, controls, and system sensitivity to surface mechanism—before you lock in a screen that hides the signal you need. Unlock real SAR:  Deconvolute potency into affinity vs. efficacy to make medicinal chemistry cycles more informative—and faster. Premium Members get a 50%+ discount when they join Terry’s Corner. 🚨 First-ever Live AMA with Dr. Kenakin  is happening September 18th, 12- 1 pm EST —exclusively inside Terry’s Corner. Bring the curve you’re debating. Ask. Challenge. Get an answer you can defend. Join Terry's Corner Today ➤ Celtarys Research – Confocal Imaging That Preserves GPCR Function Confocal imaging can clarify GPCR localization, trafficking, and dynamics—if your probes preserve function, minimize phototoxicity, and work in both live and fixed contexts. This applied article walks through ligand-directed labeling, SNAP/Halo tags, and fluorescent ligands tied to pharmacophores—plus how to choose probes for your biological context and temporal resolution. Expect practical guidance on TR-FRET compatibility, photobleaching resistance, and 3D stack acquisition for tissue-like environments. Why it matters now: Cleaner signal:  Selective excitation + low background reduces false positives in trafficking and clustering studies. Physiological relevance:  Fluorescent ligands can retain receptor integrity—critical when signaling readouts drive decisions. Assay flexibility:  Combine self-labeling tags with quantitative readouts (e.g., TR-FRET) to expand mechanism insight. Read the article here ➤ Discovery on Target 2025 – GPCR Speaker Spotlight DOT 2025 (Sept 22–25, Boston) is set to be a high-signal GPCR forum—bridging biased signaling, allostery, and structure-guided design across oncology, metabolic, CNS, and fibrosis programs. This week, get to know Dr. Aaron McGrath from Takeda. He joins Dr. Yamina Berchiche to discuss: 🔹 Why PAR1 and PAR2 are such unique GPCRs 🔹 What structural biology is teaching us about shallow orthosteric pockets and druggability 🔹 The role of cryo-EM in capturing fully activated GPCR complexes 📅 Catch Aaron’s full talk at Discovery on Target, Sept 24–25 in Boston. 🎥 Plus, join us at the GPCR Track, GPCR Happy Hour, and more! Register now and save with code SPK200 ➤ Why Dr. GPCR Premium Membership Gives You an Edge Premium delivers curated, noise-free intelligence every week: deep-dive expert lectures, classified industry news, priority event alerts, vetted job opportunities, and insider commentary—structured to help you move faster and make cleaner decisions. It’s built for scientists and leaders who want the signal, not the scroll: frameworks that clarify mechanism, context that sharpens strategy, and a community that accelerates collaboration. FAQ: Premium Membership 🔹 What’s included? The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, biotech discovery teams, platform company leaders, and decision-makers who need fast, curated, career-relevant intelligence to stay ahead. 🔹 Why now? GPCR innovation is accelerating. Those acting on the right signals today will shape tomorrow’s breakthroughs—and avoid delays others won’t see coming. 👉 Don’t Fall Behind—Access the Edge You Need 👉 Already a Premium Member? Access this week’s full Premium Edition here ➤ What our members say 🗣️ "The best pharmacology teacher teaming up with the best GPCR community platform to help train and inspire the next generation of scientists. Also super-valuable for those of us learning how to teach pharmacology." — DrGPCR University Attendee Ready to turn ambiguous signals into confident, defensible decisions—and join a community designed to move science forward? 🚀 Join Premium Today ➤

Flow cytometry, a laser-based method, is used to examine single cells suspended in a fluid. By measuring the way these cells scatter light and emit fluorescence, they can be identified, quantified and isolated into distinct cell populations. Antibody staining is a technique that helps differentiate cells and has been used in flow cytometry for a long time. In order to expand its role in GPCRs, which antibodies tend to have more trouble binding to. Fluorescent ligands based on small molecules bind to the functional sites of receptors in live cells, no need for cell fixation or permeabilization. This facilitates the study of receptor dynamics, ligand binding and signaling in real time. Figure 1.  Schematic representation of the flow cytometry technique. Adapted from Drescher H, Weiskirchen S, Weiskirchen R. Flow Cytometry: A Blessing and a Curse. Biomedicines. 2021 Nov 4;9(11):1613.   Using Fluorescent Ligands Over Antibodies in Flow Cytometry Assays: Key Advantages These are key limitations of antibody staining in flow cytometry: 1.       No need for fixation and permeabilization This step can modify receptor conformation and affect downstream signaling. 2.       Antibody batch-to-batch differences Antibodies from different lots may show different characteristics. 3.       Specificity issues Some antibodies bind to shared epitopes across different proteins, which may lead to nonspecific staining. These limitations can impact data quality, reproducibility, and assay flexibility. Fluorescent ligands  provide some key advantages  that may solve these issues: 1.       Direct binding to functional sites They bind to the active site of the receptor, which also proves kinetic and binding affinity information, not just presence. 2.       Compatibility with live cells No need for fixation of permeabilization. Ideal for live cell low cytometry, which means you can monitor while preserving cellular integrity. 3.       Higher specificity and reproducibility Well characterized ligands show consistent and selective binding to their target, lowering background noise. How Fluorescent Ligands Transform Flow Cytometry in GPCR Analysis GPCRs are a tough target in traditional antibody staining due to their membrane localization, low expression and complex conformations. Using the advantages enumerated previously, fluorescent ligands provide new capabilities: -            Real time tracking they allow continuous observation of GPCR interactions and following internalization and recycling upon activation. -            High-throughput applications Bright and stable fluorescent ligands can be used in HTS, fast tracking the assessment of GPCR interactions and signaling pathways. -            Biased signaling detection Biased pharmacophores may be used in conjunction with fluorescent tags to study biased signaling pathways, improving our understanding of GPCR functional diversity and their therapeutic potential. These capabilities help with the quantification of functional receptor expression, following internalization, analyzing ligand-receptor interactions, which are not as detectable with antibodies. Innovations in the fluorophore tags, such as pH sensitive probes, can further improve signal-to-noise ratio and reduce background interference. Optimizing Fluorescence Channels and Fluorophore Selection for GPCR-Targeted Flow Cytometry The fluorophore tag is a key part of the flow cytometry assay, as there are several key factors to be considered: 1.       Tag brightness and stability:  the brighter and more stable the better the assay outcome. 2.       Emission spectra and overlap : cell autofluorescence is usually found in the green region of the emission spectra, so using distinct fluorophores closer to red simplifies the process. 3.       Autofluorescence and multiplexing: Using far-red or near-infrared fluorophores can reduce background and support multi-parametric assays. 4.       Instrument compatibility: Fluorophores should match the laser and detector configurations of the cytometer. The optimization of fluorescence channels  is also important. The compatibility of fluorophore and detector is key to ensure a clean signal. Innovations such as spectral flow cytometry and fluorescence lifetime imaging also expand the capabilities of these tags. Fluorescent ligands are an advancement for flow cytometry applications in the GPCR field, as they overcome many limitations of the antibody-based methods. At Celtarys, we support this transition by offering optimized fluorescent ligands specifically designed for GPCR targets , including CELT-240 for hD2/D3 dopamine receptors and CELT-483 for the hσ1/σ2 sigma receptor. In addition, we provide detailed protocols and expert guidance to help you achieve reliable, actionable flow cytometry results.  Figure 2 . CELT-240 in flow cytometry binding assays is suitable to measure the affinity of compounds for the D2/D3 receptors. Flow Cytometry validation performed in the Oncological Pharmacology Laboratory of the University of Turin.    References Drescher H, Weiskirchen S, Weiskirchen R. Flow Cytometry: A Blessing and a Curse. Biomedicines. 2021 Nov 4;9(11):1613. doi: 10.3390/biomedicines9111613 University of Virginia Flow Cytometry Facility. Critical Aspects of Staining Cells [Internet]. Charlottesville (VA): University of Virginia; [cited 2025 May 16]. Available from: https://med.virginia.edu/flow-cytometry-facility/wp-content/uploads/sites/170/2015/10/Critical-Aspects-of-Staining-Cells.pdf Böhme I, Beck-Sickinger AG. Illuminating the life of GPCRs. Cell Commun Signal. 2009 Jul 14;7:16. doi: 10.1186/1478-811X-7-16  Siddiqui S, Livák F. Principles of Advanced Flow Cytometry: A Practical Guide. Methods Mol Biol. 2023;2580:89-114. doi: 10.1007/978-1-0716-2740-2_5

If you’ve ever stared at a dose–response curve and wondered, “Is this partial agonism? Or something allosteric?” —you already know the trap. In discovery, different pathways may look identical at first glance. This week in Terry's Corner you'll learn how model-based thinking helps you determine a drug’s mechanism of action and turn assay snapshots into real predictions. And here’s the danger: if you can’t tell how  a drug is working, every downstream decision—SAR, lead optimization, even clinical strategy—rests on shaky ground. You don’t need more data—you need a way to translate snapshots into predictions. This session gives you exactly that. By the end, you’ll know how to use pharmacological models to separate lookalikes, explain puzzling outcomes, and make predictions that guide discovery forward, not sideways. In This Session, You’ll Gain: ✅ How to turn descriptive snapshots into predictive insights ✅ Tools to distinguish orthosteric vs. allosteric mechanisms ✅ A framework for using models to design better experiments From Observation to Prediction You’ve run your experiment. A compound shifts the curve. It elevates the baseline. But what does that really mean? The first trap in discovery is stopping at description. You can say what the drug “seems” to do, but not what it will do elsewhere. Models are the bridge. They take descriptive data from one system and translate it into parameters that can be applied to others. Suddenly, your snapshot becomes a forecast . Instead of saying, “This looks like partial agonism” , you can ask: What happens if concentration increases further? What happens when receptor expression is different? What happens in vivo? With a model, you don’t guess. You project. When Two Mechanisms Look the Same Some of the most difficult calls in pharmacology happen when two different mechanisms look identical in a single assay . Without the right model, it’s like staring at identical twins—you can’t tell them apart until you see them move. Take the example Terry highlights: an agonist curve with a rightward shift and elevated baseline. That could be: An orthosteric partial agonist , or An allosteric partial agonist The raw data won’t tell you which. But the model will . Extend the concentration range, and the predictions diverge: Orthosteric? The shift continues linearly. Allosteric? The shift plateaus once the allosteric site saturates. With the right model, you can separate lookalikes and prevent an entire program from being misclassified. When Binding Increases Instead of Decreases Another trap: paradoxical results. You add a non-radioactive analog of a ligand, expecting it to displace binding. Instead, binding increases. Without a framework, this looks like an assay error. With a model, it becomes explainable: if the dimer form has higher affinity, then adding ligand actually drives up bound species. This isn’t noise. It’s signal—once the model interprets it. Models as Experimental Guides Models don’t just interpret results. They design experiments. In HIV entry studies, purified gp120 was too expensive for routine assays. The question was: could crude gp120 supernatant be used instead, without corrupting results? A model answered: yes—provided CD4 concentrations stayed low and gp120 concentrations high. The outcome? Reliable results at a fraction of the cost. When data alone are ambiguous, models tell you which parameters to control, which conditions to vary, and where to focus your resources. Think of models as your GPS—they don’t just explain where you are, they guide you to the next best turn. Are Models Ever Proven? Here’s the uncomfortable truth: you can never prove a model “right.” But you can build confidence through iteration. The cycle is simple: Experiment → Model → Prediction → Experiment. Each loop tightens the fit. Internal checks (like requiring a Schild regression slope of unity for competitive antagonism) add further discipline. The goal isn’t perfection. The goal is reliability : enough confidence in the model to make predictions that hold across systems. Garbage In, Garbage Out Even the best models can only work with the data they’re fed. Poor-quality data in means poor-quality predictions out. Potency (EC₅₀) is a prime example. It’s a ratio of affinity and efficacy. If you stop at potency, structure–activity relationships (SARs) may look flat. But if you deconvolute into affinity and efficacy, a rich SAR emerges. Chemists suddenly have meaningful levers to pull. The lesson: models don’t just need data. They need the right data . A Case That Seemed Impossible In one real program, a compound produced four completely different assay signatures depending on the system: Sometimes it shifted curves left Sometimes it raised baseline activity Sometimes it boosted the maximum response Chemists were left asking: Which effect should we believe? Only when the data were fit to the right model did the picture snap into focus. What looked like four conflicting behaviors turned out to be one coherent mechanism , hidden in plain sight. That’s the power of model-driven thinking—it takes chaos and reveals consistency. What You’ll Walk Away With By the end of this session, you won’t just “know about models.” You’ll know how to use them to sharpen discovery decisions. Specifically, you’ll be able to: Convert descriptive assay snapshots into predictive insights Differentiate orthosteric vs. allosteric mechanisms with confidence Apply models to design cost-efficient, informative experiments This is more than learning concepts. It’s learning how to design, interpret, and decide with models built in . Determining Mechanism of Action: Your Edge If you’re still relying on descriptive observations—“looks like a shift,” “seems like baseline activation”—you’re leaving risk on the table. With the right models, you’ll know (not guess) how your drug works, how it differs from others, and how it will behave across systems. This isn’t just another lecture. It’s a shift in how you approach discovery. Model-driven discovery accelerates timelines, prevents misclassifications, and gives your team sharper levers to pull. That’s your competitive edge. Unlock “Mechanism of Action” now Only in Terry’s Corner   Why Terry’s Corner When early choices determine which programs advance, you can’t afford vague models or slow learning. Terry’s Corner is designed to give you the edge. Join for: Weekly, faculty-grade lessons that sharpen techniques you actually deploy A continuously expanding, searchable on-demand library Monthly Ask-Me-Anything sessions  (first one coming in the next few weeks!) Subscriber-driven topics,  so the next lesson addresses your bottleneck. Built for discovery-phase teams, pharmacologists refining fundamentals, scientists challenging legacy assumptions, and leaders who need decision-ready intelligence. The pace of GPCR innovation is accelerating—teams acting on today’s insights will set tomorrow’s standards while others play catch-up. Stay current. Stay confident. Stay ahead. 🟢 40 years of expertise at your fingertips: Explore the complete library ➤ ✳️ Want to know what’s inside? Read the latest articles ➤ Stay sharp between lectures. Subscribe to The Kenakin Brief today ➤

Watch Episode 173 A rejection letter ended his dream of becoming a physician-scientist. But for Ajay Yekkirala, that closed door lit the fuse for a career that would reimagine GPCR therapeutics — and lead to two biotech startups. What followed was a scientific journey that now spans two biotech startups, and a bold reimagining of GPCR-targeted therapeutics. In this episode, he shares his career story — one that begins with a failed goal, but ends up reshaping how we think about GPCR-targeted therapeutics. His work spans deep academic research, startup life, and the application of machine learning and pharmacology to GPCR drug discovery. More than a technical overview, this is a story of curiosity, persistence, and using science to meet unmet clinical needs, especially in the chronic pain and addiction space. The Role of Mentorship and Collaboration Initially set on a career in medicine, Ajay’s plan was to pursue an MD/PhD and become a physician-scientist. But when that route closed unexpectedly, he pivoted into a PhD program at the University of Minnesota. Throughout his career, Ajay benefited from mentors who not only guided his science, but challenged him to think strategically and translationally. For his postdoctoral training at Boston Children’s Hospital and Harvard Medical School, he joined the lab of Dr. Clifford Woolf, a leader in pain biology. There, Ajay expanded his understanding of neurobiology and translational research models, further refining his interest in bridging molecular insights with therapeutic design. This environment helped him see science as an ecosystem, where collaboration and interdisciplinary thinking were essential. He also began to think more deeply about the systemic barriers that slow down or prevent good science from reaching patients — particularly in underfunded fields like pain. Blue Therapeutics: Turning GPCR Biology Into a Business Ajay’s academic training planted the seeds for what would later become Blue Therapeutics, a startup he co-founded to develop non-addictive pain medications. The company’s scientific approach relied on targeting GPCRs — specifically opioid receptors — using biased agonists that could activate beneficial pathways while avoiding harmful ones. Starting Blue wasn’t glamorous. It was investor rejections, endless slide decks, and the steep learning curve of biotech business. But it was also a crucible: Ajay learned that science doesn’t matter if you can’t convince the world to believe in it. Launching Blue was Ajay’s first hands-on experience with biotech entrepreneurship. Moving from the lab to the business world required new skills: translating biological insight into investor-ready narratives, navigating startup fundraising, and building an operational team. The transition wasn’t without friction, but it gave him the ability to test science in a translational, real-world context — something he felt academia didn’t always support. The goal of Blue wasn’t just to publish or patent; it was to bring a novel, safer class of pain therapeutics to patients — an urgent need in the midst of the opioid crisis. Superluminal Medicines: AI/ML Meets GPCR Pharmacology As Ajay continued to explore how GPCR signaling could be leveraged for therapeutic innovation, he saw a gap in the drug discovery landscape. Despite decades of progress in structural biology and pharmacology, predicting how  a GPCR will respond to a given ligand — and what downstream effects it will trigger — remained incredibly complex. To address this, he co-founded Superluminal Medicines , a biotech company focused on integrating machine learning with structural and functional GPCR data. The company’s goal is to model receptor dynamics — including biased signaling — to predict drug behavior with greater accuracy and specificity. In July 2025, Superluminal Medicines announced advancing a selective, biased, MC4R agonist small molecule to IND-enabling studies for the treatment of Obesity. Where high-throughput screening saw chaos, Ajay saw patterns waiting to be decoded. Superluminal is building systems that learn from receptor movement, conformational shifts, and complex protein-protein interactions. By making receptor behavior computationally predictable, Ajay and his team are working to reduce the time and cost of developing new, more precise GPCR-targeted therapeutics. In August 2025, Superluminal Medicines announced a collaboration with Eli Lilly and Company to advance small molecule therapeutics for cardiometabolic diseases and obesity. Lessons From the Front Lines of Biotech Ajay’s experience in both early-stage biotech and academic science has given him a broad perspective on what it takes to innovate. He emphasizes that building a startup is not simply a continuation of research — it requires a mindset shift. The stakes are different. The pressures are different. But the core is still the same: solve a hard problem that matters. He also stresses that failure — whether scientific, personal, or organizational — is a feature, not a bug. From his early career redirection to startup setbacks, each step has added new layers to his thinking about drug development. Rather than being discouraged by challenges, he views them as forcing functions for creativity and growth. Advice for Young Scientists For early-career researchers, Ajay’s journey offers a powerful blueprint. He encourages scientists to think beyond the traditional academic path and to stay close to the problems they care most about solving. Whether it's chronic pain, addiction, or another unmet need, keeping the real-world impact in focus can clarify career decisions and research priorities. He also underscores the value of developing cross-functional skills — including communication, strategy, and leadership — especially for those considering biotech or entrepreneurial ventures. The ability to ask precise, translational questions is just as important as having technical expertise. Takeaway: Ajay Yekkirala’s story is not just about GPCR science or startup success. It’s about how moments of redirection — even disappointment — can open new paths to impact. By staying grounded in scientific rigor while embracing the tools of business and technology, he’s built a career that bridges the lab bench and the clinic. Ajay's career is proof that in science, the detours are often the real path forward