Visible-Light Photoswitchable Benzimidazole Azo-Arenes as β-Arrestin2-Biased Selective Cannabinoid 2 Receptor Agonists.

Autor: Steinmüller SAM; Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany., Fender J; Institut für Pharmakologie und Toxikologie, Julius-Maximilians-Universität Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany., Deventer MH; Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium., Tutov A; Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany., Lorenz K; Institut für Pharmakologie und Toxikologie, Julius-Maximilians-Universität Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany.; Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., Bunsen-Kirchhoff-Straße 11, 44139, Dortmund, Germany., Stove CP; Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium., Hislop JN; School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, AB25 2ZD, UK., Decker M; Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2023 Dec 04; Vol. 62 (49), pp. e202306176. Date of Electronic Publication: 2023 Jul 13.
DOI: 10.1002/anie.202306176
Abstrakt: The cannabinoid 2 receptor (CB 2 R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway-selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB 2 R "efficacy-switch". Benzimidazole azo-arenes offer huge potential for the broad extension of photopharmacology to a wide range of optically addressable biological targets. We used this scaffold to develop compound 10 d, a "trans-on" agonist, which serves as a molecular probe to study the β-arrestin2 (βarr2) pathway at CB 2 R. βΑrr2 bias was observed in CB 2 R internalization and βarr2 recruitment, while no activation occurred when looking at Gα 16 or mini-Gα i . Overall, compound 10 d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB 2 R-βarr2 dependent endocytosis.
(© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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