"Photo-Rimonabant": Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar "-On" CBR Antagonist.

Human cannabinoid receptor type 1 (CBR) plays important roles in the regulation of appetite and development of addictive behaviors. Herein, we describe the design, synthesis, photocharacterization, molecular docking, and characterization of "photo-rimonabant", i.e., azo-derivatives of the selective CBR antagonist SR1411716A (rimonabant). By applying azo-extension strategies, we yielded compound , which shows marked affinity for CBR ( = 29 nM), whose potency increases by illumination with ultraviolet light (CBR K/ ratio = 15.3). Through radioligand binding, calcium mobilization, and cell luminescence assays, we established that is highly selective for CBR over CBR. These selective antagonists can be valuable molecular tools for optical modulation of CBRs and better understanding of disorders associated with the endocannabinoid system.