advertisement
Abstract #106370 Published in IGR 23-3
Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593
Brandt AL; Garai S; Zagzoog A; Hurst DP; Stevenson LA; Pertwee RG; Imler GH; Reggio PH; Thakur GA; Laprairie RBFrontiers in pharmacology 2022; 13: 919605
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 -enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the -enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the and -enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both and . The -enantiomers (GAT1665 and GAT1667) produced ago-PAM effects , and PAM effects in the behavioral triad, indicating that the activity of these ligands may occur 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.
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
Full article