학술논문
Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy
Document Type
Article
Author
Garai, Sumanta; Leo, Luciana M.; Szczesniak, Anna-Maria; Hurst, Dow P.; Schaffer, Peter C.; Zagzoog, Ayat; Black, Tallan; Deschamps, Jeffrey R.; Miess, Elke; Schulz, Stefan; Janero, David R.; Straiker, Alex; Pertwee, Roger G.; Abood, Mary E.; Kelly, Melanie E. M.; Reggio, Patricia H.; Laprairie, Robert B.; Thakur, Ganesh A.
Source
Journal of Medicinal Chemistry; 20210101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9vs threo, (±)-10constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9enantiomers, (−)-(S,R)-13evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (−)-(S,R)-13and (+)-(R,S)-14were devoid of undesirable side effects (triad test), and (+)-(R,S)-14reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (−)-(S,R)-13docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.