Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists
Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists
复制标题
激动剂和拮抗剂对 G 蛋白偶联受体 84 (GPR84) 的调节
DOI：
10.1021/acs.jmedchem.0c01378
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发表时间：
2020-12-24
影响因子：
7.3
通讯作者：
Nan, Fa-Jun
中科院分区：
文献类型：
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作者：
Chen, Lin-Hai;Zhang, Qing;Nan, Fa-Jun
自从发现中链脂肪酸作为GPR 84配体以来，GPR 84激动剂和拮抗剂的开发已经取得了重大进展。大多数激动剂具有脂质样结构，除了3，3 '-二吲哚基甲烷（DIM），其充当变构激动剂。巨噬细胞中的GPR 84活化导致细胞因子分泌、趋化性和吞噬作用增加，揭示了GPR 84与各种炎症反应相关的促炎作用。三种GPR 84拮抗剂（S）-2-（（1，4-二氧六环-2-基）甲氧基）-9-（环丙基乙炔基）-6，7-二氢-4H-嘧啶并[6，1-a]异喹啉-4-酮（GLPG 1205），钠2-（3-戊基苯基）乙酸酯（PBI-4050）和钠2-（三、5-二戊基苯基）乙酸酯（PBI-4547）已经在几种炎性和纤维化疾病的动物模型中显示出治疗效果，并且正在临床研究中进行评估。虽然GLPG 1205在溃疡性结肠炎的临床试验中失败，但它正在进行另一项针对特发性肺纤维化的II期临床研究。需要进一步的研究来解析GPR 84的结构，鉴定更多的内源性配体，阐明其生理和病理作用，并实现GPR 84拮抗剂和激动剂的治疗潜力。
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.