Discovery of Potent and Brain-Penetrant GPR52 Agonist that Suppresses Psychostimulant Behavior.

ABSTRACT: The G protein-coupled receptor 52 (GPR52) is an orphan receptor that is selectively expressed in the striatum and regulates various brain functions through activation of cAMP-dependent pathways. GPR52 has been identified as a promising therapeutic target for central nervous system disorders including schizophrenia and substance use disorders. Here, a series of novel GPR52 agonists were designed, synthesized, and evaluated based on compound 4. Several potent and efficacious GPR52 agonists (12c, 23a, 23d, 23e, 23f, and 23h) were identified with nanomolar range potency based on a systematic structure-activity relationship exploration. Further studies of 12c indicate enhanced efficacy, excellent target selectivity, and pharmacokinetic pro

SUBMITTER: Wang P 

PROVIDER: S-EPMC8428802 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature