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April 2022 Applying Allosteric Modulator Pharmacology to Treat Dyskinesia and Other Movement Disorders Co-Founder and CEO of Addex Therapeutics, which is focusing on the pharmacology known as allosteric modulation This emerging class of small molecule drugs known as allosteric modulators is being explored for treating Addex did not invent allosteric modulation but is pioneering the screening technologies to find these

Industry insights:  Crinetics' Palsonify gains momentum in acromegaly, a key indicator for pipeline expansion Gain a competitive edge:  Learn to leverage restricted diffusion and rebinding to create drugs with longer GPCR Podcast : The Future of GPCR Drug Discovery with Molecular Modeling The field of GPCR research is Learn how his research aims to develop models that can distinguish between active and inactive ligands

The conformational landscapes analyzed by Markov state models revealed that the overall conformation

can regulate GPCR/14-3-3 signals temporally, suggesting a new approach for GPCR drug development by modulating

insight straight to discovery-phase scientists and R&D strategists — without the noise, hype, or outdated models In this session, you’ll gain: ✅ Proven strategies  to balance in vitro vs. in vivo testing early — when Allosteric modulators and biased ligands aren’t exotic outliers—they’re increasingly common outcomes Biased antibodies and allosteric antibody modulators are no longer theoretical—they exist. Key Questions Answered in this AMA Session How early in vivo models sharpen go/no-go calls.

In this lesson, you’ll gain: A strategic view of how chemical scaffolds shape pharmacologic outcomes Extracts from plants, fungi, bacteria, and environmental microorganisms provided the first potent modulators This enables: Positive Allosteric Modulators (PAMs) — enhance natural signaling Negative Allosteric Modulators They offer high specificity , favorable safety , and unique mechanisms , including GPCR modulation through Subscribers gain weekly lectures led by Dr.

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 We aimed to exploit other mamba venoms to enlarge the V2R-Kunitz peptide family and gain insight into the MQ1 molecular mode of action. Conclusions and implications: A new function and mode of action is associated with the Kunitz peptides

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

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

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

GPCR Podcast : From Personal Pain to Scientific Purpose: Alex Serafini’s Journey We sit down with Dr. Serafini’s early struggles with chronic pain sparked a career focused on innovating where pain management His work challenges outdated targets, explores overlooked roles of GPCRs and RGS proteins in pain, and seeks to redefine translational models for patient realities. Explore blind spots:  The underestimated role of GPCRs and RGS proteins in chronic pain mechanisms.

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 coupling — and whether the molecular glue framing offers a productive framework for targeting gain- and 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

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

What You’ll Gain Spot false confidence early  → Sensitivity differences can turn full agonists into partials

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

In this session, you’ll gain: A clear conceptual map of Schild analysis and its origins. 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

Additionally, new studies reveal how phosphorylation barcodes shape arrestin engagement, a biased NTSR1 modulator targets pain without the need for opioids, and a real-time lipid probe tracks early signaling events Terry Kenakin, these five modules reveal how location bias, intracellular signaling, and ligand kinetics GRK-Specific Phosphorylation Barcodes Shape Arrestin Engagement with ACKR3   A β-Arrestin-2-Biased NTSR1 Modulator for Non-Addictive Pain Relief   A Cell-Permeable Fluorescent Probe Illuminates Early PI(4,5)P₂ Dynamics

Dysregulation of RGS proteins has been implicated in a range of diseases, including cardiovascular disease, pain Relating to pain, RGS4 in pain regulation is a topic of increasing interest because it has been identified as a key player in the modulation of nociception[7]. as a Potential Target for Pain Management. Avrampou, K., et al., RGS4 Maintains Chronic Pain Symptoms in Rodent Models.

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

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

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

leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain Our previous work demonstrated that GPR3-mediated β-arrestin signaling modulates amyloid-β (Aβ) generation Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological leads to a decrease in the area and compaction of amyloid plaques in the preclinical AppNL-G-F AD mouse model

that contains various adhesion-related domains and a highly-conserved GPCR-autoproteolysis-inducing (GAIN GPR125 (ADGRA3), an orphan adhesion GPCR, has been shown to modulate planar cell polarity in gastrulating The cleavage appears to occur at an atypical GPCR proteolysis site within the GAIN domain during an early

Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception "Pain The current frontline approach for pain-management is the use of opioid analgesics. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation

membrane of cells, they have easier access to the receptors than those that need to get into the cells to modulate The activation of these pathways regulates pain modulation, memory consolidation, motor coordination neuroprotective functions and is now being investigated for its role in Parkinson’s disease and neuropathic pain Of the traditional GPCRs, CBRs are gaining ground as potential therapeutic targets in several CNS diseases

Internal and external modulation factors of the orexin system (REVIEW). Multi-omics integration analysis of GPCRs in pan-cancer to uncover inter-omics relationships and potential Function Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain Structure-based pharmacophore modeling 2. Developing a novel framework for structure-based pharmacophore model generation and selection.