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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.919605

DOI=10.3389/fphar.2022.919605

ISSN=1663-9812

ABSTRACT=<p>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 <italic>R</italic>-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the <italic>S</italic>-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the <italic>R</italic> and <italic>S</italic>-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both <italic>in vitro</italic> and <italic>in vivo</italic>. The <italic>R</italic>-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects <italic>in vitro</italic>, and PAM effects in the <italic>in vivo</italic> behavioral triad, indicating that the <italic>in vivo</italic> activity of these ligands may occur <italic>via</italic> 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.</p>