The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2

被引：22
|
作者：
Dolles, Dominik [1 ]
Strasser, Andrea [2 ]
Wittmann, Hans-Joachim [2 ]
Marinelli, Oliviero [3 ]
Nabissi, Massimo [3 ]
Pertwee, Roger G. [4 ]
Decker, Michael [1 ]
机构：
[1] Julius Maximilian Univ Wurzburg, Inst Pharm & Food Chem, Pharmaceut & Med Chem, Wurzburg, Germany
[2] Univ Regensburg, Inst Pharm, Pharmaceut & Med Chem 2, Regensburg, Germany
[3] Univ Camerino, Dept Expt Med, Sch Pharm, Camerino, Italy
[4] Univ Aberdeen, Inst Med Sci, Sch Med Med Sci & Nutr, Aberdeen, Scotland
来源：
ADVANCED THERAPEUTICS | 2018年 / 1卷 / 01期
关键词：
azobenzene; benzimidazole; CB2; efficacy; photopharmacology; OPTICAL CONTROL; CB2; RECEPTOR; LIGANDS; PHARMACOLOGY; DERIVATIVES; INHIBITORS;
D O I：
10.1002/adtp.201700032
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
The hCB(2)R plays an important in the immune system and is centrally expressed in microglia. The hCB(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 hCB(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 hCB(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 GTP. S assay. cAMP ELISA and the change in expression level of two genes regulated by CREB proves that the compounds act as partial agonists.
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页数：6
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