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Extracts from plants, fungi, bacteria, and environmental microorganisms provided the first potent modulators Kenakin highlights how hybrid molecules  — combining two pharmacophores into one scaffold — enable dual-modality This enables: Positive Allosteric Modulators (PAMs) — enhance natural signaling Negative Allosteric Modulators Functionally selective ligands Better therapeutic windows More predictable clinical behavior Allosteric modulation They offer high specificity , favorable safety , and unique mechanisms , including GPCR modulation through

April 2022 Addex Expands Pipeline With Selective M4 Positive Allosteric Modulator Program For The Treatment Psychotic Disorders "New Series of Potent and Selective Compounds Identified Using Proprietary Allosteric Modulator Therapeutics (SIX: ADXN and Nasdaq: ADXN), a clinical-stage pharmaceutical company pioneering allosteric modulation-based announced today that it has moved a selective and potent M4 muscarinic receptor positive allosteric modulator

August 2022 A new Kunitz-type snake toxin family associated with an original mode of interaction with other mamba venoms to enlarge the V2R-Kunitz peptide family and gain insight into the MQ1 molecular mode Conclusions and implications: A new function and mode of action is associated with the Kunitz peptides

requires a tethered agonist-mediated activation mechanism "The mechanistic details of the tethered agonist mode ) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model

July 2022 Confo Therapeutics receives €1.7 million VLAIO grant for further research on GPCR modulators

In the current report we present evidence of the modulation of PK2/PKR2 activity by anosmin 1, since cysteine-rich (CR) and the FnIII.1 domains could assist the WAP domain both in the binding to PKR2 and in the modulation

2026 GPCR Pharmacology AMA: Receptor Theory, Biased Signaling & Assay Interpretation The first GPCR Pharmacology AMA of 2026  at Terry’s Corner will take place on: Thursday, February 26 at 1 PM EST Dr. Kenakin will address receptor theory, assay interpretation, biased signaling, and practical drug discovery challenges — driven by questions from the community. These sessions focus on real scientific uncertainty, not rehearsed presentations. Terry’s Corner Expands to YouTube Terry’s Corner is now on YouTube. Three videos are already live, and the channel will expand regularly. The objective is straightforward: Make mechanistic pharmacology easier to access, revisit, and apply across research teams. Short conceptual breakdowns Focused receptor theory discussions Clear explanations reinforcing disciplined interpretation As the archive grows, it becomes a searchable extension of Terry’s teaching — designed for repeated exposure rather than one-time viewing. Subscribe to stay current as new videos are released: ▶️ https://www.youtube.com/@TerryPharmacologyCorner New White Paper on GPCR Biased Signaling Terry Kenakin, Ph.D., Professor of Pharmacology at the University of North Carolina School of Medicine, has authored a new white paper in collaboration with Eurofins DiscoverX: Assess GPCR Biased Signaling of Agonists Using Functional Cell-Based Assays The paper explores: Detection and quantification of signaling bias Influence of biased signaling on therapeutic profiles Application of quantitative tools such as transduction coefficients (log(τ/KA) or log(max/EC50)) Systematic comparison of biased agonists using modern functional assays For scientists working in GPCR programs, this connects functional assay data directly to translational decision-making — moving beyond descriptive bias claims toward quantitative rigor. Access the white paper here Why Terry’s Pharmacology Corner Mechanistic understanding evolves. What appears settled under one experimental condition may require refinement under another. What seems definitive during early screening can shift as assay systems, receptor expression levels, or kinetics change. Pharmacology does not drift because data are missing. It drifts when interpretation becomes casual. Terry’s Pharmacology Corner provides a structured environment to maintain interpretive discipline: Weekly advanced pharmacology lectures Monthly live AMAs for real-time scientific discussion A continually expanding on-demand archive Sustained exposure to quantitative receptor theory and mechanistic reasoning The value lies not in a single explanation, but in preserving rigor as programs mature. Forty years of pharmacological expertise — organized into a year-round framework for serious GPCR scientists. Stay in the Know If you want updates on future AMAs, new YouTube releases, white papers, and ongoing pharmacology insights, join Terry Kenakin’s Brief . Concise. Focused. Mechanistic. 👉 Sign up here Continue the Work Live sessions are one layer. Sustained exposure is where judgment sharpens. If you want structured, year-round access to Terry’s full library — including advanced lectures, archived AMAs, and quantitative pharmacology deep dives: 👉 Access Terry’s Corner Free for 7 Days Strengthen Your Mechanistic Thinking

We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR

What if a seemingly “clean” antagonist profile reflects silent allosteric modulation? However, negative allosteric modulators (NAMs) with modest cooperativity can mimic orthosteric competition Key diagnostic considerations: Curved Schild plots suggest occupancy-limited modulation Linear plots affinity-dominant from efficacy-dominant agonists Detecting silent partial agonism Extracting operational model Only allosteric modulators alter the onset or offset of agonist responses.

Also this week: Terry Hébert previews his April 16 session on iPSC-derived translational models, and GPCR Selectivity: Allosteric Modulators as Intracellular Molecular Glues Standard models attribute signaling This session with Bryan Roth will cover how intracellular modulation controls G protein and arrestin extend GPCR pharmacology into disease-relevant environments, with dilated cardiomyopathy as a concrete model chemical space across target classes, with downstream integration demonstrated in a structure-based modeling

proteins in regulating basal, dopamine-induced and cAMP/PKA-dependent transcription in rat striatal neurons The activity of striatal medium-spiny projection neurons is regulated by D1 and D2 dopamine receptors whether BET proteins, or Brd4 specifically, are involved in transcriptional activation by cAMP/PKA in neurons JQ1 treatment downregulated expression of many GPCRs and also impaired ERK1/2 signalling in striatal neurons , and delineate complex bi-directional effects of bromodomain inhibitors on neuronal transcription.

September 2022 β2-Adrenergic Receptor Expression and Intracellular Signaling in B Cells Are Highly Dynamic during Collagen-Induced Arthritis "The sympathetic nervous system (SNS) has either a pro-inflammatory or anti-inflammatory effect, depending on the stage of arthritis. In the past, treatment of arthritic B cells with a β2-adrenergic receptor (β2-ADR) agonist has been shown to attenuate arthritis. In this study, the expression and signaling of β2-ADR in B cells during collagen-induced arthritis (CIA) were investigated to provide an explanation of why only B cells from arthritic mice are able to improve CIA. Splenic B cells were isolated via magnetic-activated cell sorting (MACS). Adrenergic receptors on B cells and intracellular β2-ADR downstream molecules (G protein-coupled receptor kinase 2 (GRK-2), β-Arrestin 2, p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB)) were analyzed at different time points in naïve and arthritic B cells with and without stimulation of β2-ADR agonist terbutaline by flow cytometry. β2-ADR-expressing B cells increase during CIA without a change in receptor density. Moreover, we observed a profound downregulation of GRK-2 shortly after induction of arthritis and an increase in β-Arrestin 2 only at late stage of arthritis. The second messengers studied (p38, ERK1/2 and CREB) followed a biphasic course, characterized by a reduction at onset and an increase in established arthritis. Stimulation of CIA B cells with the β-ADR agonist terbutaline increased pp38 MAPK independent of the timepoint, while pERK1/2 and pCREB were enhanced only in the late phase of arthritis. The phosphorylation of p38 MAPK, ERK1/2 and CREB in the late phase of arthritis was associated with increased IL-10 produced by B10 cells. The change of β2-ADR expression and signaling during sustained inflammation might be an integral part of the switch from pro- to anti-inflammatory action of sympathetic mechanisms in late arthritis." Read more at the source #DrGPCR #GPCR #IndustryNews

their transducer coupling, biased angiotensin receptor ligands, and circuit-selective analgesia in pain models Separate effect size from time:  Use allosteric modulators to expand therapeutic index and reduce overdose

Most GPCR programs don’t fail because of weak molecules—they fail because biology behaves differently than the assay implied. This week’s feature goes straight to the foundation: how system-level GPCR thinking  protects discovery teams from the costly misinterpretations that derail programs. If your work touches GPCR pharmacology, these insights aren’t optional—they’re essential. Breakthroughs this week: Eli Lilly cuts Zepbound prices; GNAI1 missense mutation study; rapid Gαs endosomal translocation. 🔍 This Week in Premium: Sneak Peek Industry insights:  Lilly cuts Zepbound prices; Lilly hits $1T valuation; Novo advances amycretin. Upcoming events:  Adhesion GPCR Workshop; GRC—Transporters, Ion Channels & GPCRs; MPGPCR Joint Satellite Meeting. Career opportunities:  Senior/Principal Scientist—GPCR Pharmacology; Principal Scientist—In Vitro Pharmacology; Research Associate—Biologics Discovery. Must-read publications:  Gαi1 neurodevelopmental mutation; Gαs endosomal signaling; primary cilia as transduction hubs. Terry’s Corner: GPCR Pharmacology Insights That Prevent Real Drug Discovery Failures Discovery collapses when teams assume stable, linear, receptor-to-response relationships. Dr. Kenakin’s AMA made the central point unmistakable: GPCR systems constantly reshape ligand behavior through coupling efficiency, receptor density, local signaling architecture, and physiological feedback loops. This is where system-level GPCR thinking  becomes a competitive advantage—long before a molecule reaches animals or patients. When you see the distortions baked into the system, you interpret your data differently and protect your program from preventable failures. What You’ll Gain Spot false confidence early  → Sensitivity differences can turn full agonists into partials or even antagonists depending on system load. Avoid misleading mechanistic labels  → NAMs, PAMs, and biased agonists behave in system-dependent ways that single assays cannot reveal. Translate potency and efficacy realistically  → Recognize when deviations reflect biology rather than compound failure. Premium Members get 67% discount when they join Terry’s Corner in 2025 Sharpen your interpretation skills ➤ Dr. GPCR Podcast: Chemical Probes for GPCR Imaging with Dr. Johannes Broichhagen Reliable imaging tools change how researchers see receptor behavior. In this episode, Dr. Johannes Broichhagen explains how next-generation fluorescent probes—designed with precise synthetic logic—enable deeper insight into GPCR internalization, trafficking, and surface organization. His work shows why chemical design can outperform antibodies and how rigorous assay validation bridges chemistry and biology effectively. What You’ll Learn Why peptide–fluorophore probes succeed where antibodies fail How parallel synthesis& testing accelerates probe optimization How surface-exposed receptor pools reshape interpretations of trafficking Listen to the episode ➤ High-Content Screening for GPCR Programs: Overcoming Assay Limitations with Fluorescent Ligands High-content screening (HCS) is now indispensable for GPCR workflows—especially when spatial context, trafficking behavior, and live-cell kinetics matter. But HCS only works when assays are built with rigor and powered by the right fluorescent ligands. This feature from Celtarys Research outlines how to structure an HCS workflow that avoids batch effects, imaging artifacts, and variability while delivering reliable, mechanistic data. What You’ll Learn Why traditional radioligand assays miss critical spatial and kinetic signals Five phases of a robust, reproducible HCS pipeline How fluorescent ligands strengthen specificity, relevance, and assay confidence Read the full HCS feature ➤ Why System-Level GPCR Thinking Changes Data Interpretation And How Dr. GPCR Premium Membership Gives You an Edge Premium gives GPCR scientists and biotech teams a single, trusted source of weekly insight that cuts through noise. Members access deep-dive lectures, expert frameworks, curated jobs, upcoming events, and classified more. It’s a system-aware resource built for researchers who need clarity fast—reinforcing system-level GPCR thinking  every week so your interpretations stay sharp and aligned with real biology. FAQ 🔹 What’s included? Weekly research, careers, and industry intelligence; GPCR University; 200+ expert talks; networking; and member-only discounts. 🔹 Who is it for? Researchers, pharmacologists, biotech teams, and decision-makers who rely on accurate, efficient, interpretation-first information. 🔹 Why now? GPCR innovation is accelerating—and misinterpretation compounds quickly. Staying informed today prevents the 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 Members Say "I am a convert! I will keep Dr. GPCR and the offered resources in my work sphere." Help us reach more scientists by providing quick rating on Spotify or Apple Podcasts — and a YouTube subscribe. Spotify: https://open.spotify.com/show/1KQHbC2qhkRIrdgBDtiQVF Apple Podcasts: https://podcasts.apple.com/us/podcast/dr-gpcr-podcast/id1514231064 YouTube: https://www.youtube.com/@DrGPCR Want to support Dr. GPCR? 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Slopes <1  may reveal allosteric modulation , where the antagonist binds at a secondary site. The model’s flexibility accommodates both agonism and antagonism as long as the analysis targets equilibrium Modern pharmacology has powerful modeling software, yet Schild analysis remains the litmus test for mechanism

Join us for the first virtual cafe talk to hear about the amazing work that Dr. Brian Arey is doing. https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe/ #gpcr #drgpcr #virtualcafe

For decades, the dominant model treated these receptors as molecular switches: ligand binds and then That model was useful, but it was also incomplete. In this article, you will learn: Why biased signaling has displaced the traditional switch model of GPCR Allosteric Modulation and the Microcircuit Model of GPCR Pharmacology Understanding GPCRs as allosteric , post-translational modifications, and dynamic pathophysiological states that no single  in vitro  model

It is one model among several, but it explains the observation cleanly, and it has practical consequences for how programs at peptide receptors approach modality choice. This model suggests the consequence. The small molecule can show affinity for the site. lecture: an orthosteric small molecule binds in only a few of the regions a peptide engages, and on this model What This Means for Program Decisions The affinity-trap account, treated as a model rather than a verdict

2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation

However, the channel is expressed in various tissues and cell types including neurons as well as glial developments with particular focus on findings from studies involving ocular tissues and cells or peripheral neurons

pipelines, and a growing number of programs moving into the clinic are redefining what's possible across modalities presenting real workflows and real data, covering generative antibody design, dynamic conformational modeling Antibodies, Cyclic Peptides & Allosteric Modulators Nine or more presentations on non-small molecule Executive Director and Head of GPCR Biology at Iambic Therapeutics, where he leads AI-driven structural modeling

Venetia Zachariou  introduced him to the power of RGS proteins — particularly RGS4  — in modulating pain recovery that is very rare to see at the preclinical level. " Such recovery is rare in preclinical pain models and hints that RGS proteins could modulate pain chronification itself .

GPCR Binders, Drugs, and more Allosteric modulation of a human odorant receptor. Single-cell transcriptome analysis of NEUROG3+ cells during pancreatic endocrine differentiation with assays allow the analysis of binding kinetics of WNT-3A to endogenous Frizzled 7 in a colorectal cancer model

in isolation—they respond to the system they’re in, often through opposing processes that you must model In this session, you’ll gain: ✅ A mental model you can trust  for predicting how GPCR ligands behave This section outlines the logic required to match preclinical models to patient physiology and avoid In this module, you’ll explore how some receptor–agonist complexes continue signaling from endosomes, Your molecule isn’t failing—your model might be too simple.

Welcome back GPCR fans, If your drug discovery strategy still relies on static GPCR models, you’re already Leverage this model to stay ahead of therapeutic complexity. It’s the 20th anniversary—and the spotlight is squarely on kinetic modeling, allosteric frameworks, and Access peer insights on allosteric modulators and biased ligands.

Before the advent of AlphaFold, homology modeling was the most common method for predicting G protein-coupled Homology modeling relies on using the known structure of a homologous protein as a template to model For proteins with low sequence similarity to available templates, homology models tend to be less accurate targeting TAAR1, more than double that of the homology models. Ligand discovery from a dopamine D3 receptor homology model and crystal structure.

Dopamine D2 receptor modulators  – transforming treatment for Parkinson’s & schizophrenia. Allosteric modulation  for unprecedented precision. Serotonin & dopamine receptor modulation  for neuropsychiatric disorders. These sessions bridge structural biology , computational modeling , and clinical translation  — with

GPCR Symposium on 'GPCRs as Therapeutic Modalities' is set for September 22nd. treatment of cardiometabolic disease GPCRs in Neuroscience Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/D2R heterodimers GPR37L1 controls diseases Ultrasensitive dose-response for asbestos cancer risk implied by new inflammation-mutation model the GPCR Smoothened and to the germline inducer Oskar Industry News Addex GABAb Positive Allosteric Modulator

Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological Current literature strongly establishes increased levels and activity of GRK2 in multiple models of CVD the GRK2 interactome includes numerous proteins which interact with differential domains of GRK2 to modulate the ongoing and future research for targeting this critical kinase across cellular, animal and human models

By modulating receptor expression or sensitivity, we can shift the “lens” through which drug activity Model patient-like pathophysiological states (e.g., reduced receptor expression in heart failure). Adjusting assay sensitivity—whether through expression systems, chemical modulation, or engineered desensitization—provides landscape is dynamic—ligands compete, cooperate, and reshape receptor ensembles in ways that standard models