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The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2
Author(s) -
Dolles Dominik,
Strasser Andrea,
Wittmann HansJoachim,
Marinelli Oliviero,
Nabissi Massimo,
Pertwee Roger G.,
Decker Michael
Publication year - 2018
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.201700032
Subject(s) - radioligand , chemistry , neuroinflammation , cannabinoid , cannabinoid receptor type 2 , receptor , cannabinoid receptor , creb , stereochemistry , pharmacology , microbiology and biotechnology , biochemistry , biology , gene , immunology , inflammation , antagonist , transcription factor
The h CB 2 R plays an important in the immune system and is centrally expressed in microglia. The h CB 2 R activated by agonists hold great therapeutic potential, e.g., in neuroinflammation. It is currently not yet elucidated how pathophysiological processes are mediated by the h CB 2 R. 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 h CB 1 R 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.