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.