Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor

Robert B. Laprairie, Pushkar M. Kulkarni, Jeffrey R. Deschamps, Melanie E.M. Kelly, David R. Janero, Maria G. Cascio, Lesley A. Stevenson, Roger G. Pertwee, Terrence P. Kenakin, Eileen M. Denovan-Wright, Ganesh A. Thakur*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1188-1203
Number of pages16
JournalACS Chemical Neuroscience
Issue number6
Early online date7 Feb 2017
Publication statusPublished - 21 Jun 2017

Bibliographical note

Funding Information:
This work was supported by a partnership grant from CIHR, Nova Scotia Health Research Foundation (NSHRF), and the Huntington Society of Canada (HSC) (ROP-97185) to E.D.W., a CIHR operating grant (MOP-97768) to M.E.M.K., and grants from NIH/National Eye Institute (EY024717 to G.A.T., R.G.P., and M.E.K.). R.B.L. is supported by studentships from CIHR, HSC, Killam Trusts and NSHRF. The X-ray crystallographic work was supported by the United States National Institutes on Drug Abuse (NIDA) through Interagency Agreement No. Y1-DA1101 with the Naval Research Laboratory.

Publisher Copyright:
© 2017 American Chemical Society.


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


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