Open Access“Photo-Rimonabant”: Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar “Cis-On” CB1R Antagonist
Author(s) -
Diego Alejandro Rodríguez-Soacha,
Julia Fender,
Yesid A. Ramírez,
Juan A. Collado,
Eduardo Muñóz,
Rangan Maitra,
Christoph A. Sotriffer,
Kristina Lorenz,
Michael Decker
Publication year - 2021
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.1c00086
Subject(s) - rimonabant , antagonist , endocannabinoid system , chemistry , cannabinoid , cannabinoid receptor , stereochemistry , docking (animal) , radioligand , cannabinoid receptor antagonist , combinatorial chemistry , pharmacology , in vitro , receptor , biochemistry , biology , medicine , nursing
Human cannabinoid receptor type 1 ( h CB 1 R) plays important roles in the regulation of appetite and development of addictive behaviors. Herein, we describe the design, synthesis, photocharacterization, molecular docking, and in vitro characterization of "photo-rimonabant", i.e., azo-derivatives of the selective h CB 1 R antagonist SR1411716A (rimonabant). By applying azo-extension strategies, we yielded compound 16a , which shows marked affinity for CB 1 R ( K i ( cis form) = 29 nM), whose potency increases by illumination with ultraviolet light (CB 1 R K i trans / cis ratio = 15.3). Through radioligand binding, calcium mobilization, and cell luminescence assays, we established that 16a is highly selective for h CB 1 R over h CB 2 R. These selective antagonists can be valuable molecular tools for optical modulation of CBRs and better understanding of disorders associated with the endocannabinoid system.