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-Gα_i . Overall, compound 10 d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB₂ R-βarr2 dependent endocytosis.