Highly Selective, Amine-Derived Cannabinoid Receptor 2 Probes.

Autor: Westphal MV; Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland., Sarott RC; Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland., Zirwes EA; Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland., Osterwald A; Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland., Guba W; Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland., Ullmer C; Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland., Grether U; Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland., Carreira EM; Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2020 Jan 27; Vol. 26 (6), pp. 1380-1387. Date of Electronic Publication: 2020 Jan 21.
DOI: 10.1002/chem.201904584
Abstrakt: 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.
(© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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