2. Academic Validation
  3. Discovery and Characterization of a Novel Small-Molecule Agonist for Medium-Chain Free Fatty Acid Receptor G Protein-Coupled Receptor 84

Discovery and Characterization of a Novel Small-Molecule Agonist for Medium-Chain Free Fatty Acid Receptor G Protein-Coupled Receptor 84

  • J Pharmacol Exp Ther. 2016 May;357(2):337-44. doi: 10.1124/jpet.116.232033.
Qing Zhang 1,  Hui Yang 1,  Jing Li 1,  Xin Xie 2
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China (Q.Z., X.X.); and CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (Q.Z., H.Y., J.L., X.X.).
  • 2 Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China (Q.Z., X.X.); and CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (Q.Z., H.Y., J.L., X.X.) xxie@simm.ac.cn.
PMID: 26962172 DOI: 10.1124/jpet.116.232033
Abstract

G protein-coupled receptor 84 (GPR84) is a Free Fatty Acid Receptor activated by medium-chain free fatty acids with 9-14 carbons. It is expressed mainly in the immune-related tissues, such as spleen, bone marrow, and peripheral blood leukocytes. GPR84 plays significant roles in inflammatory processes and may represent a novel drug target for the treatment of immune-mediated diseases. However, the lack of potent and specific ligands for GPR84 hindered the study of its functions and the development of potential clinical applications. Here, we report the screen of 160,000 small-molecule compounds with a calcium mobilization assay using a human embryonic kidney 293 cell line stably expressing GPR84 and Gα16, and the identification of 2-(hexylthio)pyrimidine-4,6-diol (ZQ-16) as a potent and selective agonist of GPR84 with a novel structure. ZQ-16 activates several GPR84-mediated signaling pathways, including calcium mobilization, inhibition of cAMP accumulation, phosphorylation of extracellular signal-regulated protein kinase 1/2, receptor desensitization and internalization, and receptor-β-arrestin interaction. This compound may be a useful tool to study the functions of GPR84 and a potential candidate for further structural optimization.

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