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J Med Chem ; 66(18): 12858-12876, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37708305

RESUMO

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 ß-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 CB1 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.


Assuntos
Agonistas de Receptores de Canabinoides , Transdução de Sinais , Humanos , Ratos , Animais , Receptores de Canabinoides , beta-Arrestinas , Corpo Estriado/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptor CB2 de Canabinoide , Receptor CB1 de Canabinoide
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