Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy

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 a-position of nitro group generated two diastereomers, the greater pot...

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Vydané v:	Journal of medicinal chemistry Ročník 64; číslo 12; s. 8104 - 8126
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	WASHINGTON Amer Chemical Soc 24.06.2021
Predmet:	Allosteric Site Animals Cannabinoid Receptor Agonists - chemical synthesis Cannabinoid Receptor Agonists - metabolism Cannabinoid Receptor Agonists - therapeutic use Chemistry, Medicinal CHO Cells Cricetulus Glaucoma - drug therapy HEK293 Cells Hippocampus - cytology Humans Indoles - chemical synthesis Indoles - metabolism Indoles - therapeutic use Intraocular Pressure - drug effects Life Sciences & Biomedicine Ligands Male Mice Mice, Inbred C57BL Molecular Conformation Molecular Docking Simulation Molecular Dynamics Simulation Neurons - drug effects Pharmacology & Pharmacy Receptor, Cannabinoid, CB1 - agonists Receptor, Cannabinoid, CB1 - chemistry Receptor, Cannabinoid, CB1 - metabolism Science & Technology Stereoisomerism Structure-Activity Relationship CB1 DRUG DISCOVERY ENDOCANNABINOID SYSTEM PROTEIN-COUPLED RECEPTORS FUNCTIONAL SELECTIVITY GENERAL FORCE-FIELD INTRAOCULAR-PRESSURE BINDING MU-OPIOID RECEPTOR AGONIST
ISSN:	0022-2623, 1520-4804, 1520-4804
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Shrnutí:	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 a-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (+/-)-9 vs threo, (+/-)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (+/-)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs beta-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-I4 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804 1520-4804
DOI:	10.1021/acs.jmedchem.1c00040