ArticleMolecular pharmacology2013
CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 112 citations in OpenAlex.
- A randomised controlled trial of vaporised ΔEuropean archives of psychiatry and clinical neuroscience · 2019Trial
- Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery.Acta pharmacologica Sinica · 2025Review
- Negative allosteric modulation of CB1 cannabinoid receptor signalling decreases intravenous morphine self-administration and relapse in mice.Addiction biology · 2024Article
- Effects of CB1 receptor negative allosteric modulator Org27569 on oxycodone withdrawal symptoms in mice.Psychopharmacology · 2024Article
- Insight into the mechanism of action of ORG27569 at the cannabinoid type one receptor utilising a unified mathematical model.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Review
- Enhanced Cytotoxicity and Antimelanoma Activity of Novel Semisynthetic Derivatives of Betulinic Acid with Indole Conjugation.Plants (Basel, Switzerland) · 2023Article
- Article
- Negative allosteric modulation of CBPharmacological research · 2022Article
- Development of 3-(4-Chlorophenyl)-1-(phenethyl)urea Analogues as Allosteric Modulators of the Cannabinoid Type-1 Receptor: RTICBM-189 is Brain Penetrant and Attenuates Reinstatement of Cocaine-Seeking Behavior.Journal of medicinal chemistry · 2022Article
- Modulation of type 1 cannabinoid receptor activity by cannabinoid by-products fromFrontiers in pharmacology · 2022Article
- CB1 Cannabinoid Receptor Signaling and Biased Signaling.Molecules (Basel, Switzerland) · 2021Review
- Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol-A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling.Molecules (Basel, Switzerland) · 2021Article
- Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.Trends in pharmacological sciences · 2021Review
- G protein-coupled receptors: structure- and function-based drug discovery.Signal transduction and targeted therapy · 2021Review
- In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa.Scientific reports · 2020Article
- Molecular Mechanism and Cannabinoid Pharmacology.Handbook of experimental pharmacology · 2020Article
- Structure of an allosteric modulator bound to the CB1 cannabinoid receptor.Nature chemical biology · 2019Article
- Dose-Dependent Cannabidiol-Induced Elevation of Intracellular Calcium and Apoptosis in Human Articular Chondrocytes.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2019Article
- Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators.Journal of medicinal chemistry · 2019Article
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
We have previously identified allosteric modulators of the cannabinoid CB(1) receptor (Org 27569, PSNCBAM-1) that display a contradictory pharmacological profile: increasing the specific binding of the CB(1) receptor agonist [(3)H]CP55940 but producing a decrease in CB(1) receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signaling endpoints linked to CB(1) receptor activation. We assessed the effect of these compounds on CB(1) receptor agonist-induced [(35)S]GTPγS binding, inhibition, and stimulation of forskolin-stimulated cAMP production, phosphorylation of extracellular signal-regulated kinases (ERK), and β-arrestin recruitment. We also investigated the effect of these allosteric modulators on CB(1) agonist binding kinetics. Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signaling as compared with WIN55212 and having little effect on [(3)H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding, simulation (Gα(s)-mediated), and inhibition (Gα(i)-mediated) of cAMP production and β-arrestin recruitment. In contrast, it acts as an enhancer of agonist-induced ERK phosphorylation. Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation. We find that in both saturation and kinetic-binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity. The data indicate that the allosteric modulators share a common mechanism whereby they increase available high-affinity CB(1) agonist binding sites. The receptor conformation stabilized by the allosterics appears to induce signaling and also selectively traffics orthosteric agonist signaling via the ERK phosphorylation pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.