Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593

Asher L Brandt; Sumanta Garai; Ayat Zagzoog; Dow P Hurst; Lesley A Stevenson; Roger G Pertwee; Gregory H Imler; Patricia H Reggio; Ganesh A Thakur; Robert B Laprairie

doi:10.3389/fphar.2022.919605

Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593

Front Pharmacol. 2022 Oct 25:13:919605. doi: 10.3389/fphar.2022.919605. eCollection 2022.

Authors

Affiliations

¹ College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
² Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Boston, MA, United States.
³ Center for Drug Discovery, University of North Carolina Greensboro, Greensboro, NC, United States.
⁴ School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
⁵ Centre for Biomolecular Science and Engineering, Naval Research Laboratory, Washington, DC, United States.
⁶ Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.

Abstract

Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo. The R-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro, and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington's disease.

Keywords: In silico modeling; allosteric agonist; molecular mechanics-generalized born surface area (MMGBSA); molecular pharmacology; positive allosteric modulator; type 1 cannabinoid receptor (CB1R).