Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists.
- Resource Type
- Academic Journal
- Authors
- 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.
- Source
- Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
- Subject
- Language
- English
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.