Discovery of R-185 as a Potent and Orally Efficacious GPR52 Agonist with Potential for Treating Schizophrenia and Related Neuropsychiatric Disorders

G protein-coupled receptor 52 (GPR52) has been identified as a promising therapeutic target for the treatment of schizophrenia, psychiatric disorders, and other human neurological diseases. A series of novel 2,3-disubstituted pyrazine derivative GPR52 agonists have been designed, synthesized, and biologically evaluated. Through the exploration of the structure–activity relationship, several potent GPR52 agonists (14a, 14h, 14l, 20c, and 20i) were identified, with EC50 values in the nanomolar range (26–70 nM). Further studies on 14h indicate that it has excellent pharmacokinetic properties in mice and rats, as well as brain permeability (brain/plasma ratio = 1.6 and 3.1, respectively). In vivo, compound 14h (R-185) significantly inhibits MK-801-induced hyperlocomotor behaviors in zebrafish larvae and mice. Overall, our research results have identified an effective, orally bioavailable, and brain-permeable GPR52 agonist (14h), which is a promising candidate for the development of antischizophrenia drugs.