Modulation of the G‑Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists

Since the discovery of medium-chain fatty acids as GPR84 ligands, significant advancements have been made in the development of GPR84 agonists and antagonists. Most agonists have lipid-like structures except for 3,3′-diindolylmethane (DIM), which acts as an allosteric agonist. GPR84 activation in ma...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-12, Vol.63 (24), p.15399-15409
Main Authors: Chen, Lin-Hai, Zhang, Qing, Xie, Xin, Nan, Fa-Jun
Format: Article
Language:English
Subjects:
Acetates - chemistry
Acetates - pharmacology
Acetates - therapeutic use
Allosteric Regulation - drug effects
Animals
Binding Sites
Humans
Idiopathic Pulmonary Fibrosis - drug therapy
Idiopathic Pulmonary Fibrosis - metabolism
Idiopathic Pulmonary Fibrosis - pathology
Inflammatory Bowel Diseases - drug therapy
Inflammatory Bowel Diseases - metabolism
Inflammatory Bowel Diseases - pathology
Isoquinolines - chemistry
Isoquinolines - pharmacology
Isoquinolines - therapeutic use
Ligands
Molecular Docking Simulation
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - metabolism
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Summary:Since the discovery of medium-chain fatty acids as GPR84 ligands, significant advancements have been made in the development of GPR84 agonists and antagonists. Most agonists have lipid-like structures except for 3,3′-diindolylmethane (DIM), which acts as an allosteric agonist. GPR84 activation in macrophages leads to increased cytokine secretion, chemotaxis, and phagocytosis, revealing the proinflammatory role of GPR84 associated with various inflammatory responses. Three GPR84 antagonists (S)-2-((1,4-dioxan-2-yl)­methoxy)-9-(cyclopropylethynyl)-6,7-dihydro-4H-pyrimido­[6,1-a]­isoquinolin-4-one (GLPG1205), sodium 2-(3-pentylphenyl)­acetate (PBI-4050), and sodium 2-(3,5-dipentylphenyl)­acetate (PBI-4547) have displayed therapeutic effects in animal models of several inflammatory and fibrotic diseases and are being evaluated in clinical studies. Although GLPG1205 has failed in a clinical trial for ulcerative colitis, it is undergoing another phase II clinical study for idiopathic pulmonary fibrosis. Further studies are needed to resolve the GPR84 structure, identify more endogenous ligands, elucidate their physiological and pathological roles, and fulfill the therapeutic potential of GPR84 antagonists and agonists.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01378