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

Abstract

AbstractThe cannabinoid 2 receptor (CB2R) 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 CB2R “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 CB2R. βΑrr2 bias was observed in CB2R 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 CB2R‐βarr2 dependent endocytosis.