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

Angew Chem Int Ed Engl. 2023 Jun 2:e202306176. doi: 10.1002/anie.202306176. Online ahead of print.

ABSTRACT

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 10d, a “trans-on” agonist, which serves as a molecular probe to study the β-arrestin2 (βarr2) pathway at CB2R. βArr2 bias was observed in CB2R internalization and ßarr2 recruitment, while no activation occurred when looking at Gα16 or mini-Gαi. Overall, compound 10d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB2R-βarr2 dependent endocytosis.

PMID:37269130 | DOI:10.1002/anie.202306176