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Understanding the Connection Between Residence Time and Drug Efficacy: The Importance of Moving Beyond In Vitro Potency. Kenakin’s latest lecture delivers a paradigm shift for pharmacologists working on drugs where in vitro potency fails to predict clinical outcomes . If your lead compounds look perfect on paper but disappoint in vivo, residence time may be the missing piece. This course redefines what makes a drug “effective,” arguing that kinetic persistence (not binding affinity) determines real-world success . From restricted tissue diffusion to PK–PD dissociation, Kenakin equips you with the kinetic models and biological context needed to design drugs that actually work where it matters: in the body. In This Session, You’ll Gain: ✅ Modeling tools to understand how restricted diffusion  in tissues like tumors slows offset and improves therapeutic window ✅ Examples of how rebinding in dense receptor environments  amplifies target occupancy, even post-clearance ✅ Insight into why half-life can be misleading  when volume of distribution hides the drug from its target When Potency Isn’t Enough Drug discovery teams are trained to chase nanomolar potency. But this metric assumes equilibrium, and equilibrium doesn’t exist in vivo. Concentrations rise and fall. Clearance happens. And drugs only work when they’re bound. Kenakin walks through cases where two equipotent ligands produce radically different clinical outcomes , not because of potency, but because of how long they stay on target. In a world of fluctuating drug levels, residence time becomes the true predictor of effect. Diffusion, Rebinding, and Receptor Density: The In Vivo Edge This lecture shows how tissue architecture alters drug action . In structured, diffusion-restricted environments (e.g. brain, tumors), drugs don't just leave slowly; they often rebind . And when receptors are dense (like GPCRs on membranes), this rebinding hits the collisional limit , where every molecular encounter leads to binding. The result? Drugs with poor pharmacokinetics can outperform flashier compounds by exploiting kinetic environments  that weren’t visible in vitro assays. PK–PD Dissociation: When Clearance Doesn’t Mean It’s Over The lecture’s standout example: Aplaviroc, an allosteric CCR5 inhibitor with rapid systemic clearance—yet near-permanent occupancy at its target. The takeaway is clear: fast clearance does not necessarily mean loss of efficacy  when binding offset is slow. This has implications for everything from dosing frequency  to resistance barriers  in infectious disease and oncology. Why Half-Life Can Lie to You Most teams use systemic half-life as a proxy for action. But as Kenakin shows, t½ is a surface metric —a combination of clearance and volume of distribution. A drug hiding in fat tissue may stay in the body for days, but if it never reaches the target site, the therapeutic effect is zero. He breaks down how to distinguish between true target persistence vs. sequestration, with clear takeaways for decision-making in lead optimization and formulation. Rebuild Your Metrics. Redefine Your Pipeline If your development program is built around potency alone, you may be leaving high-value compounds behind. Residence time provides a second dimension of drug evaluation , one that explains results in animal models, informs clinical translation, and helps teams avoid late-stage surprises. Kenakin offers not just theory, but tools to model, predict, and validate this behavior early. Unlock “Target Residence Time” Now Only in Terry’s Corner Why Terry’s Corner In a world where drug discovery is evolving faster than most can track, Terry’s Corner is your shortcut to staying ahead . Here’s what members get: Weekly deep dives from Dr. Terry Kenakin Monthly Ask‑Me‑Anything sessions with live Q&A An expanding on‑demand library for novices to expert drug hunters Influence over future topics Access to the study group Whether you’re in hit-to-lead, lead optimization, or clinical pharmacology strategy, this is where 40 years of kinetic expertise meet the real questions you’re asking in the lab. Don’t just keep pace—outpace the field. 🟢 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 ➤ #TargetResidenceTime #DrugBindingKinetics #PKPDdissociation #ReceptorPharmacology #InVivoPharmacology #KineticPharmacology #LeadOptimization #Pharmacokinetics #Pharmacodynamics #TissueDiffusion #DrugRebinding #ResidenceTimeMatters

Watch Episode 171 Mentoring in science is more than supervising—it’s about shaping the next generation. In this podcast episode , Alessandro Nicoli shares how becoming the first PhD student in a new lab shaped his view of leadership, teamwork, and scientific growth. Starting From Zero: Growing With a Mentor When Alessandro joined Prof. Antonella Di Pizio’s lab , there was almost nothing—no team, no culture, not even proper desks. But that experience gave him a unique sense of ownership. As the lab grew, so did his responsibilities: from building computational models of GPCRs to guiding interns, master’s students, and even giving lectures . “I remember my first day—we were even sharing the desk. Over the years you see the lab establishing, and for both of us, of course, growing.”  —Alessandro Nicoli Delegating Is a Process Learning to delegate was not easy. Alessandro admits he struggled at first with handing over parts of his projects, fearing mistakes. “It’s a process that is still going on. At the start it was difficult, because you see all these projects and you think, ah, I don’t know… but then with time, of course, it’s a lot of investment.”  —Alessandro Nicoli He discovered that investing time in people pays off. Mistakes are part of learning—and guiding students through them is more valuable than doing everything alone. Leadership as Shared Growth For Alessandro, mentorship is not about control but about growing together . Students bring fresh perspectives, and in teaching them, he also sharpens his own skills. “You can guide them to learn the technique and go over it. But at the same time, you pass the same struggle before… you shape the new generation too.”  —Alessandro Nicoli This two-way growth has turned mentoring into one of his favorite parts of PhD life. Ready to mentor—or to be mentored? Join the GPCR scientist network and connect with peers shaping the next wave of discovery. ________ Keyword Cloud: #Mentoring #ScienceLeadership #PhDmentorship #GPCR #PhDlife #AcademicLeadership #LabCulture #TrainingScientists

Elevate Your GPCR Science with Essential Frameworks for Precision Drug Discovery: An Insight into Advanced Strategies for Targeted Therapeutics. Welcome back GPCR lovers, In pharmacology, the wrong interpretation of antagonist behavior can derail your conclusions, your experiments, and even your program’s credibility. That’s why mastering competitive vs non-competitive antagonism isn’t optional — it’s essential for accurate, defensible science. This week, Terry’s Corner takes you beyond curve shapes into the kinetic and mechanistic realities that separate surface-level analysis from true expertise. Breakthroughs this week: FFA4 receptor signaling controls lipolysis at lipid droplets; novel atypical GPCR-arrestin complexes; Lilly's oral GLP-1, orforglipron, delivers weight loss of up to an average of 27.3 lbs in first of two pivotal Phase 3 trials in adults with obesity. 🔍 This Week in Premium: Sneak Peek A quick look at the curated intelligence our Premium members are using to stay ahead this week: Industry insights:  The latest on how AI is being used to unlock elusive GPCR targets, financial results from Neurocrine Biosciences, and a deep dive into Crinetics Pharmaceuticals’ oral acromegaly drug. We’re also tracking major pipeline clearouts and the competitive landscape for oral GLP-1 drugs. Upcoming events:  An exclusive preview of the “neuroGPCR: G protein coupled receptor signaling in its physiological cellular context” symposium and our featured talk at the upcoming Discovery on Target 2025 conference. Career opportunities:  A curated list of new positions, including a Research Associate, a Senior Research Scientist, and a Post-doctoral Researcher position focused on GPCRs and Mitochondria. Must-read publications:  New insights on RGS protein modulation, GRK2-biased β₂AR signaling, and the distinct role of GRK3 in platelet activation. We’ve also highlighted the latest research on non-canonical internalization mechanisms of mGlu receptors and the intrinsic signaling bias of GPR52. Terry's Corner - Demystifying Antagonism: The Key to Precision Drug Discovery Understanding the nuances of competitive versus non-competitive antagonism is a cornerstone of effective drug discovery. Without a solid grasp of these concepts, scientists risk misinterpreting critical data, leading to flawed decisions and wasted resources. This week in Terry’s Corner , we go beyond the dose-response curves to explore the kinetic and pharmacologic signatures of antagonism. Dr. Kenakin’s expert guidance provides a clear framework for distinguishing these mechanisms and avoiding common pitfalls that can derail a program. Don't let misconceptions about receptor binding kinetics slow your progress—gain the clarity you need to move forward with confidence. Solve the problem of misinterpreting your data by understanding how slow-offset kinetics can mimic classical patterns, leading to incorrect mechanistic assignments. Gain a competitive edge by asking the right questions about binding kinetics and experimental constraints, ensuring your analysis is robust and your decisions are sound. Avoid the professional threat of flawed data interpretations that can lead to costly dead ends and missed opportunities in your drug discovery program. Premium Members get 50%+ discount when they join Terry’s Corner. Sharpen your discovery decisions ➤ Yamina's Consulting Corner - Building Your GPCR Program for Breakthroughs, Not Breakdowns In the fast-paced world of GPCR drug discovery, the "go fast" mindset can often lead to costly breakdowns. Yamina’s Corner tackles the critical disconnect between brilliant science and operational strategy, revealing why throwing more money and people at a problem is a multi-million dollar mistake. This week, we introduce a new series, "The GPCR Precision Blueprint," which provides a systematic framework to ensure your science, strategy, and execution are seamlessly aligned. Learn how to transform your program from a series of disconnected efforts into a predictable, de-risked pathway to success. Solve the problem of a fragmented approach by learning how to build a unified system where every scientific detail and strategic decision aligns. Gain a competitive edge by transforming your GPCR data from chaos into a strategic asset, enabling faster, more confident decision-making. Avoid the professional threat of financial friction and missed investment opportunities by learning to translate operational precision into a compelling narrative for stakeholders. Three takeaways from this week’s feature: Stop firefighting:  Learn why solving isolated problems burns capital without fixing root causes. Bridge science and strategy:  Ensure data and decision-making align with funding and milestones. Build predictable success:  Use a repeatable improvement framework to turn operational chaos into precision execution. Read the full article here ➤ Insights from the Field: The Next Wave of GPCR Drug Discovery The 20th annual GPCR-Based Drug Discovery conference is where the future of GPCR therapies will be defined. If you’re not there, you’re missing out on the next wave of allosteric modulators, biased ligands, and computational targeting. This event is a critical opportunity to stay informed, but the real advantage lies in applying these insights to your work. Our weekly curated news and expert frameworks provide the actionable intelligence you need to make sense of these trends and integrate them into your own research. Solve the problem of information overload by getting a curated summary of the key talks and discussions from the event. Gain a competitive edge by staying on top of the latest breakthroughs in allostery, biased signaling, and computational pharmacology. Avoid the professional threat of falling behind your peers by accessing the same insights that are driving the next generation of drug discovery. Register and join your colleagues in September ➤ Why Dr. GPCR Premium Membership Gives You an Edge In a world filled with noise, Dr. GPCR Premium Membership delivers curated, noise-free intelligence every week. We provide deep-dive expert lessons, classified industry news, priority event alerts, job opportunities, and insider commentary—all designed to help you move faster, smarter, and with greater confidence. This isn’t just information; it’s a strategic framework for your career. Our content is meticulously vetted and organized to provide clarity and actionable insights that you can apply immediately to your work, helping you avoid costly missteps and capitalize on emerging opportunities. FAQ 🔹 What’s included? The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, exclusive on-demand expert frameworks, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, biotech drug 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. Don’t Fall Behind—Access the Edge You Need 👉 Become a Premium Member Today ➤ Already a Premium Member? 👉 Access this week’s full Premium Edition here ➤ Hear What Our Members Are Saying “The content had enough depth to satisfy the hunger for theory while being full of practical knowledge.” - DrGPCR University Course Attendee Get a competitive advantage—Join Dr. GPCR Premium Today The breakthroughs are happening now, and the decisions you make today will determine your professional trajectory. Don’t wait for others to lead the way. Join the community of informed, empowered GPCR professionals who are shaping the future of drug discovery. Gain the insights, tools, and connections you need to excel in your field and make your mark. Keywords: GPCR, drug discovery, pharmacology, antagonism, competitive, non-competitive, Terry's Corner, Yamina's Corner, biotech, systems thinking, signal transduction, operational excellence, drug development, pharmaceutical, scientific career Hashtags: #DrGPCR #GPCR #DrugDiscovery #Pharmacology #Biotech #GPCRNews #Science #DrugDevelopment

Advance your GPCR research career with Dr. GPCR University. Access 20+ on-demand GPCR courses, 200+ expert talks, weekly news, and a global scientist network. Join Premium today. Strategic Partners Dr. GPCR University Empowering Scientists to Advance GPCR Therapeutics Learn faster. Connect deeper. Drive discoveries. Join the only global platform dedicated to GPCR scientists. Become a Premium Member Why Join? 20+ on-demand GPCR courses created by leading experts Complete GPCR coverage – news, papers, jobs, industry updates Weekly GPCR News with full expert commentary 200+ recorded expert talks across discovery & therapeutics Community tools – connect directly with scientists worldwide Career Matchmaker: Finding your perfect role or employee. ↪ For scientists who want structured training + insider knowledge beyond papers. 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GPCR Activation and Signaling Expert talks on GPCR signaling, ligand bias and deorphanization Structural and Molecular Insights into GPCR Activation Exploring β-adrenergic signaling, CCR5 regulation, and Kappa opioid receptor selectivity Summit 2022 Topics include GPCR mutations, receptor interactions, and drug discovery technologies GPCRs in Immunology and Oncology Roundtable discussion on GPCRs role in immunology and cancer research GPCR Activation and Signaling Topics include chemokine receptor signaling, biased agonism, and anti-GPCR antibodies Summit 2021 Topics include GPCR activation, heteromers, and structure-based drug discovery GPCRs as Therapeutic Modalities Innovative GPCR therapeutic approaches, from psychedelics to selective ligands Recent Advances in Understanding Challenging GPCRs Exploring orphan GPCRs, adhesion receptors, and unconventional signaling pathways Summit 2020 Discussions include GPCR signaling, drug discovery, and innovative pharmacology View all 200+ Expert Talks Join us and enjoy 15+ GPCR-focused scientific talks. 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Expert support, trusted CROs, and ready-to-use tools to accelerate GPCR drug discovery, reduce risk, and advance your discovery-stage projects. Dr. GPCR Foundry Accelerate Your GPCR Discovery Program Built for GPCR biotech companies advancing discovery-stage projects — access expert support, trusted GPCR CROs, ready-to-use tools, and specialist guidance tailored to your goals. Everything you need to move faster and reduce risk in GPCR drug discovery. Get expert guidance on your next project this week. Unlock Biotech Solutions What is Dr. GPCR Foundry? Dr. GPCR Foundry is your hub for advancing GPCR discovery programs. Help your GPCR biotech company to find the right expertise, validate partners, plan smarter, and execute with confidence — all in one place. We connect you to: Specialist consultants Trusted GPCR CROs Proven timelines Upskilling resources Media opportunities for visibility Who is the Foundry for? GPCR biotech companies working on discovery-stage programs who need guidance, support, or specialist partners — wherever you are in your journey, we meet you where you are. You need Foundry if you're: ✔ A GPCR biotech startup validating your first target ✔ An established biotech looking to scale ✔ See king credible GPCR CROs for discovery-stage work Explore Resources for GPCR Biotech Companies Uncover blind spots and make smarter decisions faster → Yamina's Corner 👉 Book a Consulting Call Sharpen skills and boost results with proven training → Dr. GPCR University 👉 Explore Training Programs Turn cutting-edge science into actionable know-how → Terry's Corner 👉 Join an Intensive Course Equip your entire team with the tools and connections to succeed → Dr. GPCR University Team Membership 👉 Upgrade Your Team Help your GPCR discovery program succeed Discovery Consulting & Strategy Trusted guidance to reduce risk and improve project planning. Visibility for GPCR CROs Media partner packages that connect CROs with biotech innovators. Training & Upskilling Specialized courses designed for discovery-phase GPCR programs. Tools & Templates Practical, ready-to-use resources tailored to discovery-stage GPCR work. ✉ Contact Us Our Partners Join these innovative organizations already benefiting from the DrGPCR Foundry. Current Partners Let's move your GPCR discovery program forward. Wherever you are in your discovery journey, the Foundry helps GPCR biotech companies move faster and reduce risk. Let's discuss your next step. Book a 30-min Strategy Call

Catherine Demery shares how she found clarity and purpose in academic opioid research. From her early doubts to designing preclinical models of fentanyl and xylazine overdose, she reflects on staying in academia, building translational experiments, and using real-world data to drive impactful science in the GPCR research community. Dr. GPCR Podcast << Back to podcast list Strategic Partners Xylazine, Fentanyl, and the Fight for Breath with Catherine Demery Two drugs. Two different mechanisms. One deadly outcome. Fentanyl and xylazine are pushing the opioid crisis into dangerous new territory, and Catherine Demery is on the front lines of the science trying to stop it. In this gripping conversation, Catherine, a PhD candidate at the University of Michigan, shares how personal loss and an unconventional career path—industry chemist, NIH researcher, and now GPCR pharmacologist—led her to investigate how these drugs shut down breathing in different ways. Her research combines cutting-edge GPCR signaling studies with real-time public health data from Michigan’s Red Project, revealing how fentanyl slows inhalation, xylazine prolongs exhalation, and together they drop heart rate to dangerous lows. And while users aren’t asking for xylazine, dealers are lacing it into the supply—driving overdose deaths higher. Why This Matters Fentanyl : Potent synthetic opioid that decreases inhalation rate. Xylazine : Veterinary sedative that prolongs exhalation and induces bradycardia—acting through alpha-2 adrenergic, not opioid, receptors. The Combo : Not just additive—lethal. Street Data : Xylazine-laced fentanyl in Michigan has jumped 30–60% in recent years. What You’ll Learn in This Episode How industry lab experience builds the discipline needed for academic research. Why xylazine is an emerging overdose threat and how it differs mechanistically from opioids. The methods used to measure respiratory depression in live models. How loss and lived experience can sharpen scientific focus. The role of public health programs in informing lab research. How GPCR pharmacology connects molecular insights to real-world interventions. Who Should Listen This episode is especially relevant for: GPCR drug discovery scientists Respiratory pharmacologists Addiction researchers Public health professionals Early-career scientists navigating non-linear paths About Catherine Demery Catherine Demery didn’t set out to be on the front lines of the opioid crisis. After earning her undergraduate degree in biochemistry from the University of Michigan, she deferred pharmacy school, unsure if that path felt right. Instead, she went hands-on—working as an analytical chemist in a GLP/GMP-regulated CRO, where precision and discipline became second nature. That led her to a master’s in pharmacogenomics at Manchester University, igniting her fascination with how genetics and drugs interact. Her next stop: the NIH, studying the immunology of pregnancy. But loss has a way of sharpening focus—friends lost to overdose brought the opioid epidemic into painful clarity. Catherine decided to act where she could make the biggest difference: in the lab. Today, as a PhD candidate in the labs of Dr. John Traynor and Dr. Jessica Anand at the University of Michigan, Catherine investigates how fentanyl and xylazine shut down breathing through different mechanisms—work that blends receptor pharmacology, preclinical models, and public health data to tackle one of the most urgent challenges in addiction science. Catherine Demery on the web LinkedIn Google Scholar University of Michigan 🎧 Listen now and see how one scientist is turning molecules into a mission, bridging the gap between receptor pharmacology and the urgent fight to save lives in the opioid epidemic. __________ Keyword Cloud GPCR research community , Dr. GPCR ecosystem , GPCR training program , GPCR podcast , opioid pharmacology , xylazine research , mu opioid receptor , pharmacogenomics , fentanyl epidemic , preclinical pharmacology Thanks for listening to this podcast episode This short survey will help us understand your needs to bring you exciting and informative content; this short survey should take 5 minutes to fill. Listen and subscribe to where you get your podcasts. << Previous Podcast Episode Next Podcast Episode >>