The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2

Abstract

The hCB2R plays an important in the immune system and is centrally expressed in microglia. The hCB2R activated by agonists hold great therapeutic potential, e.g., in neuroinflammation. It is currently not yet elucidated how pathophysiological processes are mediated by the hCB2R. Here, photochromic affinity switches based on a drugable benzimidazole core through azologization and computational studies are developed. Structure-activity relationships (SARs) lead to compounds with high selectivity over hCB1R that can be reversibly switched to a higher affinity cis-form proved on the receptor level by radioligand binding studies and translating into an affinity change in a functional GTPγS assay. cAMP ELISA and the change in expression level of two genes regulated by CREB proves that the compounds act as partial agonists.