Visible-light photoswitchable benzimidazole azo-arenes as β-arrestin2-biased selective cannabinoid 2 receptor agonists

The 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 & beta;-arrestin2 (& beta;arr2) pathway at CB2R. & beta;& UAlpha;rr2 bias was observed in CB2R internalization and & beta;arr2 recruitment, while no activation occurred when looking at G & alpha;(16) or mini-G & alpha;(i). Overall, compound 10 d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB2R-& beta;arr2 dependent endocytosis.