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Synthesis and biological evaluation of novel photoswitchable molecules derived from Rimonabant lead to a highly selective and nanomolar "Cis-On" CB1R antagonist
Rodriguez-Soacha, D. A., Fender, J., Ramirez, Y. A., Antonio Collado, J., Munoz, E., Maitra, R., Sotriffer, C., Lorenz, K., & Decker, M. (2021). "Photo-Rimonabant": Synthesis and biological evaluation of novel photoswitchable molecules derived from Rimonabant lead to a highly selective and nanomolar "Cis-On" CB1R antagonist. ACS Chemical Neuroscience, 12(9), 1632-1647. https://doi.org/10.1021/acschemneuro.1c00086
Human cannabinoid receptor type 1 (hCB(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 hCB(1)R antagonist SR1411716A (rimonabant). By applying azo-extension strategies, we yielded compound 16a, which shows marked affinity for CB1R (K-i (cis form) = 29 nM), whose potency increases by illumination with ultraviolet light (CB1R K(i)trans/cis ratio = 15.3). Through radioligand binding, calcium mobilization, and cell luminescence assays, we established that 16a is highly selective for hCB(1)R over hCB(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.
