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ACS Chem Neurosci. 2017 Jun 21;8(6):1188-1203. doi: 10.1021/acschemneuro.6b00310. Epub 2017 Feb 7.

Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor.

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Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
Naval Research Laboratory , Code 6930, 4555 Overlook Avenue, Washington, D.C. 20375, United States.
Center for Drug Discovery; Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Department of Chemistry and Chemical Biology, College of Science, and Health Sciences Entrepreneurs; Northeastern University , Boston, Massachusetts 02115, United States.
School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen , Aberdeen AB25 2ZD, Scotland, U.K.
Department of Pharmacology, University of North Carolina School of Medicine , Chapel Hill, North Carolina 27599, United States.


The cannabinoid 1 receptor (CB1R) is one of the most widely expressed metabotropic G protein-coupled receptors in brain, and its participation in various (patho)physiological processes has made CB1R activation a viable therapeutic modality. Adverse psychotropic effects limit the clinical utility of CB1R orthosteric agonists and have promoted the search for CB1R positive allosteric modulators (PAMs) with the promise of improved drug-like pharmacology and enhanced safety over typical CB1R agonists. In this study, we describe the synthesis and in vitro and ex vivo pharmacology of the novel allosteric CB1R modulator GAT211 (racemic) and its resolved enantiomers, GAT228 (R) and GAT229 (S). GAT211 engages CB1R allosteric site(s), enhances the binding of the orthosteric full agonist [3H]CP55,490, and reduces the binding of the orthosteric antagonist/inverse agonist [3H]SR141716A. GAT211 displayed both PAM and agonist activity in HEK293A and Neuro2a cells expressing human recombinant CB1R (hCB1R) and in mouse-brain membranes rich in native CB1R. GAT211 also exhibited a strong PAM effect in isolated vas deferens endogenously expressing CB1R. Each resolved and crystallized GAT211 enantiomer showed a markedly distinctive pharmacology as a CB1R allosteric modulator. In all biological systems examined, GAT211's allosteric agonist activity resided with the R-(+)-enantiomer (GAT228), whereas its PAM activity resided with the S-(-)-enantiomer (GAT229), which lacked intrinsic activity. These results constitute the first demonstration of enantiomer-selective CB1R positive allosteric modulation and set a precedent whereby enantiomeric resolution can decisively define the molecular pharmacology of a CB1R allosteric ligand.


7-transmembrane receptor; Allosteric regulation; G-protein-coupled receptor; cannabinoid; cellular signaling; central nervous system; ligand bias; molecular pharmacology; probe dependence; receptor activation; therapeutics discovery

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