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

Abstract

The cannabinoid 2 receptor (CB2 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 CB2 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 CB2 R. βΑrr2 bias was observed in CB2 R internalization and βarr2 recruitment, while no activation occurred when looking at Gα16 or mini-Gαi . Overall, compound 10 d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB2 R-βarr2 dependent endocytosis.

• Authors: Sophie A M Steinmüller, Julia Fender, Marie H Deventer, Anna Tutov, Kristina Lorenz, Christophe P Stove, James N Hislop, Michael Decker
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 62 Issue 49 Pg. e202306176 (12 04 2023) ISSN: 1521-3773 [Electronic] Germany
• PMID: 37269130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Chemical References

• beta-Arrestin 2
• Cannabinoid Receptor Agonists
• Cannabinoids
• Benzimidazoles

Topics

• beta-Arrestin 2 (metabolism)
• Cannabinoid Receptor Agonists
• Cannabinoids (pharmacology)
• Benzimidazoles (chemistry)