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

Abstract

Human cannabinoid receptor type 1 (<i>h</i>CB₁R) plays important roles in the regulation of appetite and development of addictive behaviors. Herein, we describe the design, synthesis, photocharacterization, molecular docking, and <i>in vitro</i> characterization of "photo-rimonabant", i.e., azo-derivatives of the selective <i>h</i>CB₁R antagonist SR1411716A (rimonabant). By applying azo-extension strategies, we yielded compound <b>16a</b>, which shows marked affinity for CB₁R (<i>K</i>_{i (<i>cis</i> form)} = 29 nM), whose potency increases by illumination with ultraviolet light (CB₁R K_i<i>trans</i>/<i>cis</i> ratio = 15.3). Through radioligand binding, calcium mobilization, and cell luminescence assays, we established that <b>16a</b> is highly selective for <i>h</i>CB₁R over <i>h</i>CB₂R. These selective antagonists can be valuable molecular tools for optical modulation of CBRs and better understanding of disorders associated with the endocannabinoid system.