“Photo-Rimonabant”: Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar “Cis-On” CB1R Antagonist

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.