Visible-Light Photoswitchable Benzimidazole Azo-Arenes as ß-Arrestin2-Biased Selective Cannabinoid 2 Receptor Agonists.
Angew Chem Int Ed Engl
; 62(49): e202306176, 2023 12 04.
Article
em En
| MEDLINE
| ID: mdl-37269130
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 ß-arrestin2 (ßarr2) pathway at CB2 R. ßΑrr2 bias was observed in CB2 R internalization and ßarr2 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-ßarr2 dependent endocytosis.
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Base de dados:
MEDLINE
Assunto principal:
Canabinoides
/
Agonistas de Receptores de Canabinoides
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article