ArticleEuropean journal of medicinal chemistry2025
Discovery of novel and selective GPR17 antagonists as pharmacological tools for developing new therapeutic strategies in diabetes and obesity.
Article in European journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- G Protein-Coupled Receptor 17 (Gpr17) Enhances Leptin and Insulin Sensitivity in Lean and Obese Mouse Models.Obesity (Silver Spring, Md.) · 2026Review
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation.Frontiers in immunology · 2026Review
- Microbiome affects mice metabolic homeostasis via differential regulation of gene expression in the brain and gut.Physiological reports · 2025Article
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10 authors.
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Abstract
G protein coupled receptors (GPCRs) are promising targets for diabetes and obesity therapy due to their roles in metabolism and excellent potential for pharmacological manipulation. We previously reported that Gpr17 ablation in the brain-gut axis leads to improved metabolic homeostasis, suggesting GPR17 antagonism could be developed for diabetes and obesity treatment. Here, we performed high throughput screening (HTS) and identified two new GPR17 antagonists (compound 978 and 527). Both compounds antagonized downstream Gαi/o, Gαq and β-arrestin signaling with high selectivity for GPR17, but not the closely related purinergic and cysteinyl leukotriene receptors. The molecular mechanisms of antagonism were revealed through Schild analysis, structure-activity relationship (SAR) studies and homology modeling. Compound 978, a competitive antagonist against the surrogate small molecule agonist MDL29,951 (MDL), and its analog (793) attenuated GPR17 signaling and promoted glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells. In summary, we identified selective GPR17 antagonists through HTS, which represent promising pharmacological tools for developing new therapeutic strategies in diabetes and obesity.
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