Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists.

Autor:	Hewer RC; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Christie LA; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Doyle KJ; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Xu X; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Roberts MJ; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Dickson L; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Cheung T; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Cadwalladr DH; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Pickford P; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Teall M; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Powell JAC; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Sheardown S; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Narayana L; Aragen Life Sciences Ltd, Plot #284A (part), Bommasandra-Jigani Link Road Industrial Area, Bengaluru 562106, India., Brice NL; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Dawson LA; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Carlton M; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K., Bürli RW; Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Sep 28; Vol. 66 (18), pp. 12858-12876. Date of Electronic Publication: 2023 Sep 14.
DOI:	10.1021/acs.jmedchem.3c00784
Abstrakt:	From our NETSseq-derived human brain transcriptomics data, we identified GPR55 as a potential molecular target for the treatment of motor symptoms in patients with Parkinson's disease. From a high-throughput screen, we identified and optimized agonists with nanomolar potency against both human and rat GPR55. We discovered compounds with either strong or limited β-arrestin signaling and receptor desensitization, indicating biased signaling. A compound that showed minimal GPR55 desensitization demonstrated a reduction in firing frequency of medium spiny neurons cultured from rat striatum but did not reverse motor deficits in a rat hypolocomotion model. Further profiling of several desensitizing and non-desensitizing lead compounds showed that they are selective over related cannabinoid receptors CB 1 and CB 2 and that unbound brain concentrations well above the respective GPR55 EC 50 can be readily achieved following oral administration. The novel brain-penetrant GPR55 agonists disclosed can be used to probe the role of this receptor in the brain.
Databáze:	MEDLINE
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