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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Published in:Journal of medicinal chemistry Vol. 64; no. 12; pp. 8104 - 8126
Main Authors: 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.
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 24.06.2021
Subjects:
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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Summary: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.
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.1c00040