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 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 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.
Activation of the human cannabinoid receptor type 1 (hCB 1 R) with high spatiotemporal control is useful to study processes involved in different pathologies related to nociception, metabolic alterations, and neurological disorders. To synthesize new agonist ligands for hCB 1 R, we have designed different classes of photoswitchable molecules based on an indole core. The modifications made to the central core have allowed us to understand the molecular characteristics necessary to design an agonist with optimal pharmacological properties. Compound 27a shows high affinity for CB 1 R (K i (cis-form) = 0.18 μM), with a marked difference in affinity with respect to its inactive "trans-off" form (CB 1 R K i trans/cis ratio = 5.4). The novel compounds were evaluated by radioligand binding studies, receptor internalization, sensor receptor activation (GRABeCB2.0), Western blots for analysis of ERK1/2 activation, NanoBiT βarr2 recruitment, and calcium mobilization assays, respectively. The data show that the novel agonist 27a is a candidate for studying the optical modulation of cannabinoid receptors (CBRs), serving as a new molecular tool for investigating the involvement of hCB 1 R in disorders associated with the endocannabinoid system.
In this report, the advances of photopharmacology as a method that allows the study of therapeutically relevant target proteins for Alzheimer's disease (AD) with high spatiotemporal resolution through photoswitchable molecules that are manipulated by light irradiation will be presented. The chemical and biophysical basics of the design of photoswitchable drugs are considered, as well as their current specific applications in the development of tool compounds to investigate functions of acetylcholinesterase, muscarinic acetylcholine, cannabinoid, and NMDA receptors, respectively. All of them represent highly important AD targets.
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