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

  • J Med Chem. 2026 Jun 11;69(11):13765-13787. doi: 10.1021/acs.jmedchem.6c00686.
Haoran Li  1  2 ,  Shuli Xia  1  2 ,  Pengqi Zhang  1  2 ,  Mengfei Li  1  2 ,  Ling Lv  1  2 ,  Xuetao Zhang  1  2 ,  Xin Li  1  2 ,  Zhiqing Liu  1  2 ,  Chang-Yun Wang  1  2 ,  Pingyuan Wang  1  2
Affiliations
  • 1. Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China.
  • 2. Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
PMID: 42200598 DOI: 10.1021/acs.jmedchem.6c00686
Abstract

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.

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