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Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.

ABSTRACT: G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate the pathophysiological role of GPR84 and to validate GPR84 as a therapeutic target. We previously reported the discovery of a novel triazine GPR84 competitive antagonist 1. Here, we describe an extensive structure-activity relationship (SAR) of antagonist 1 and also present in silico docking with supporting mutagenesis studies that reveals a potential binding pose for this type of orthosteric antagonist. Lead compound 42 is a potent GPR84 antagonist with a favorable pharmacokinetic (PK) profile suitable for further drug development.

SUBMITTER: Mahindra A

PROVIDER: S-EPMC9421653 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.

Mahindra Amit A Jenkins Laura L Marsango Sara S Huggett Mark M Huggett Margaret M Robinson Lindsay L Gillespie Jonathan J Rajamanickam Muralikrishnan M Morrison Angus A McElroy Stuart S Tikhonova Irina G IG Milligan Graeme G Jamieson Andrew G AG

Journal of medicinal chemistry 20220810 16

G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate the pathophysiological role of GPR84 and to validate GPR84 as a therapeutic target. We prev ...[more]

PMID: 35948061

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Project description:This study evaluated the effect of maternal glycerol monolaurate (GML) supplementation during late gestation and lactation on sow reproductive performance, transfer of immunity and redox status, milk fat and fatty acid profile, and fecal microbiota. Eighty multiparous sows (Landrace × Large white) were randomly allocated to two treatment groups (with or without 1000 mg/kg GML) with 40 replicates per treatment. The feeding experiment lasted from d 85 of gestation (G85) to d 23 of lactation (L23). The samples were collected on d 1 (L1) and 21 (L21) of lactation. Our results showed that maternal GML supplementation significantly increased litter weight (P = 0.002), average daily gain of piglets (P = 0.048), and sow average daily feed intake (P = 0.032). Compared with CON group, the concentrations of lauric acid (C12:0; P = 0.022), C16:0 (P = 0.001), and total saturated fatty acids (P = 0.006) in colostrum as well as C12:0 in L21 milk (P = 0.001) were higher in GML group. Besides, the concentrations of immunoglobulin A (IgA) and IgG in colostrum as well as sow and piglet plasma, the total antioxidant capacity and superoxide dismutase activity in sow colostrum were also significantly higher in the GML group (P < 0.05). Microbiome results showed that GML addition increased fecal microbial alpha diversity as well as the relative abundances of short chain fatty acids producing bacteria Ruminococcaceae and Parabacteroides; and decreased the harmful Proteobacteria of sows (P < 0.05). The Spearman analysis showed that the microbial biomarkers Prevotellaceae, Ruminococcaceae, and Parabacteroides were positively correlated with IgA and IgG of sow plasma and milk (P < 0.05). Besides, maternal GML addition up-regulated the relative protein expressions of proliferating cell nuclear antigen, cyclin D1, G protein-coupled receptor 84 (GPR84) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in the duodenum and jejunum of piglets. Collectively, current findings suggested that maternal GML supplementation enhanced piglet growth during lactation, which might be associated with improving milk fat and lauric acid contents, microbiota derived immunoglobulins transfer, and gut health through potential involvement of GPR84 and PI3K/Akt signaling pathway.

Dataset Information

Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.

Publications

Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.

Similar Datasets

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