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

Abstract

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.

Design, synthesis and biological evaluation of light-driven on–off multitarget AChE and MAO-B inhibitors

“…This leads to high concentration of the active compound in the irradiated site, which subsequently and irreversibly follows its pharmacokinetic path; 25 2) conjugation of the bioactive molecule with well-known molecular photoswitches, first of all azobenzene. [25][26][27] The photoinduced change produces variations in the geometry, polarity, and spatial position of functional groups by modulating the affinity of the compound for the target binding site. The photoisomerizable accessory fragments allow the bioactive species to be reversibly activated and/or deactivated, simply by modulating the power and wavelength of the light source used.…”

Die Erhellung des “Bewusstseinsmoleküls”: Photomodulation des 5‐HT2A Rezeptors durch ein licht‐steuerbares N,N‐Dimethyltryptamin‐Derivat

“…Photoschaltbare Liganden, d. h. Moleküle, die reversibel ihre chemische Struktur (Abbildung 2A) und gleichzeitig ihre biologische Wirkung nach Bestrahlung mit Licht ändern, ermöglichen es, Licht mit seiner unvergleichbar guten raumzeitlichen Präzision als externen Stimulus zu verwenden. Für zahlreiche Zielstellungen erwiesen sich Azobenzol‐basierte photoschaltbare Liganden als wirksame molekulare Werkzeuge zur Untersuchung von ansonsten sehr schwer aufklärbarer Prozesse [9–23] …”

Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools

“…1 H NMR (500 MHz, CDCl 3 ) δ 8.01 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 6.5 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.58−7.34 (m, 8H), 7.26−7.19 (m, 2H), 5.12 (d, J = 6.3 Hz, 2H), 3.89 (t, J = 7.3 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.23 (s, 3H), 1.66−1.58 (m, 2H), 1.39−1.31 (m, 2H), 1.18−1.09 (m, 2H). 13 (12). Yellow oil, 36%.…”

“…Optical control provides spatiotemporal tools for understanding and regulating complex biochemical processes. , Photopharmacology has emerged in recent years and has found broad application in reversible modulation across various biological targets, such as ion channels, , enzymes, , transporters, , receptors, − and others. Small-molecule-based photopharmacology is made possible using ligands that are integrated with photoswitches that facilitate the translation of the input optical signals into various pharmacological output signals.…”