“Photo-Rimonabant”: Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar “<i>Cis</i>-On” CB<sub>1</sub>R Antagonist
Diego A. Rodríguez‐Soacha, Julia Fender, Yesid A. Ramírez, Juan A. Collado, Eduardo Muñóz, Rangan Maitra, Christoph Sotriffer, Kristina Lorenz, Michael Decker
Abstract
Human cannabinoid receptor type 1 (hCB1R) 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 hCB1R antagonist SR1411716A (rimonabant). By applying azo-extension strategies, we yielded compound 16a, which shows marked affinity for CB1R (Ki (cis form) = 29 nM), whose potency increases by illumination with ultraviolet light (CB1R Kitrans/cis ratio = 15.3). Through radioligand binding, calcium mobilization, and cell luminescence assays, we established that 16a is highly selective for hCB1R over hCB2R. These selective antagonists can be valuable molecular tools for optical modulation of CBRs and better understanding of disorders associated with the endocannabinoid system.