Biased agonists of GPR84 and insights into biological control

Abstract

GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell types with the highest levels of expression being in innate immune cells, M1 polarised macrophages and neutrophils. The first reported ligands for this receptor were medium chain fatty acids with chain lengths between 9 and 12 carbons. Subsequently a series of synthetic agonists that signal via the GPR84 receptor were identified. Radioligand binding assays and molecular modelling with site‐directed mutagenesis suggest the presence of three ligand binding sites on the receptor, but the physiological agonist(s) of the receptor remain unidentified. Here, we review the effects of GPR84 agonists on innate immune cells following a series of chemical discoveries since 2001. The development of highly biased agonists has helped to probe receptor function in vitro, and the remaining challenge is to follow the effects of biased signalling to the physiological functions of innate immune cell types.

Structure–Activity Relationship Studies and Optimization of 4-Hydroxypyridones as GPR84 Agonists

“…Recruitment of β-arrestin is linked to receptor desensitization and internalization but may also mediate to a range of other effects . Apart from implication of internalization, the role of β-arrestin signaling in GPR84 is still unclear . We probed the ability of selected compounds (ZQ-16, DL-175, 4a , 4f , 4i , 4s , 42a ) to promote internalization of a fluorescently tagged GPR84 at concentrations corresponding to EC 90 from the β-arrestin recruitment assay and at 98 μM (100 × EC 90 from the GTPγS assay) for DL-175 that did not show an effect in this assay.…”

“…57 Apart from implication of internalization, the role of β-arrestin signaling in GPR84 is still unclear. 58 We probed the ability of selected compounds (ZQ-16, DL-175, 4a, 4f, 4i, 4s, 42a) to promote internalization of a fluorescently tagged GPR84 at concentrations corresponding to EC 90 from the β-arrestin recruitment assay and at 98 μM (100 × EC 90 from the GTPγS assay) for DL-175 that did not show an effect in this assay. Microscopy of the cells at 0 and 15 min (SI, Figure S1) shows that activation of β-arrestin translates to internalization for all compounds, whereas DL-175 did not show evidence of receptor internalization.…”

Editorial for GPR84 pharmacology

“…David Greaves (University of Oxford) described the development of LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc this ligand as well as a series of further, highly potent GPR84 activators with even more extensive bias (Luscombe et al, 2024). Compared with 6-n-octylaminouracil, DL-175 fails to promote chemotaxis in LPS-stimulated U937 macrophages, whereas both these ligands do so in human monocytes.…”