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Highly Selective, Amine‐Derived Cannabinoid Receptor 2 Probes
Author(s) -
Westphal Matthias V.,
Sarott Roman C.,
Zirwes Elisabeth A.,
Osterwald Anja,
Guba Wolfgang,
Ullmer Christoph,
Grether Uwe,
Carreira Erick M.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201904584
Subject(s) - cannabinoid , endocannabinoid system , cannabinoid receptor , chemistry , receptor , synthetic cannabinoids , g protein coupled receptor , cannabinoid receptor type 2 , pharmacology , biochemistry , combinatorial chemistry , stereochemistry , biology , antagonist
Abstract The endocannabinoid (eCB) system is implied in various human diseases ranging from central nervous system to autoimmune disorders. Cannabinoid receptor 2 (CB 2 R) is an integral component of the eCB system. Yet, the downstream effects elicited by this G protein‐coupled receptor upon binding of endogenous or synthetic ligands are insufficiently understood—likely due to the limited arsenal of reliable biological and chemical tools. Herein, we report the design and synthesis of CB 2 R‐selective cannabinoids along with their in vitro pharmacological characterization (binding and functional studies). They combine structural features of HU‐308 and AM841 to give chimeric ligands that emerge as potent CB 2 R agonists with high selectivity over the closely related cannabinoid receptor 1 (CB 1 R). The synthesis work includes convenient preparation of substituted resorcinols often found in cannabinoids. The utility of the synthetic cannabinoids in this study is showcased by preparation of the most selective high‐affinity fluorescent probe for CB 2 R to date.