1. Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists.
- Author
-
Hewer RC, Christie LA, Doyle KJ, Xu X, Roberts MJ, Dickson L, Cheung T, Cadwalladr DH, Pickford P, Teall M, Powell JAC, Sheardown S, Narayana L, Brice NL, Dawson LA, Carlton M, and Bürli RW
- Subjects
- Humans, Rats, Animals, Receptors, Cannabinoid, beta-Arrestins, Corpus Striatum metabolism, Receptors, G-Protein-Coupled metabolism, Receptor, Cannabinoid, CB2, Receptor, Cannabinoid, CB1, Cannabinoid Receptor Agonists, Signal Transduction
- Abstract
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 CB2 and that unbound brain concentrations well above the respective GPR55 EC50 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.- Published
- 2023
- Full Text
- View/download PDF