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GPR84 is an orphan G-protein-coupled receptor that is expressed on immune cells and implicated in several inflammatory diseases. The validation of GPR84 as a therapeutic target is hindered by the narrow range of available chemical tools and consequent poor understanding of GPR84 pathophysiology. Here we describe the discovery and characterization of DL-175, a potent, selective, and structurally novel GPR84 agonist and the first to display significantly biased signaling across GPR84-overexpressing cells, primary murine macrophages, and human U937 cells. By comparing DL-175 with reported GPR84 ligands, we show for the first time that biased GPR84 agonists have markedly different abilities to induce chemotaxis in human myeloid cells, while causing similar levels of phagocytosis enhancement. This work demonstrates that biased agonism at GPR84 enables the selective activation of functional responses in immune cells and delivers a high-quality chemical probe for further investigation.

Original publication

DOI

10.1021/acschembio.9b00533

Type

Journal article

Journal

ACS Chem Biol

Publication Date

20/09/2019

Volume

14

Pages

2055 - 2064

Keywords

Animals, CHO Cells, Cell Line, Tumor, Chemotactic Factors, Cricetulus, Cyclic N-Oxides, Humans, Macrophages, Mice, Molecular Structure, Phagocytosis, Pyridines, Quantitative Structure-Activity Relationship, Receptors, G-Protein-Coupled, Signal Transduction