Small‐molecule ligands are envisaged to occupy a “classical” site encapsulated in the 7TM bundle. Molecular docking to a homology model suggested a site for lipid binding, predicting the acyl side‐chain to extend into the membrane bilayer between TM4 and TM5 of GPR132. The synthetic cannabinoid CP‐55 940 also activates GPR132. A telmisartan analog, GSK1820795A, antagonizes the actions of N‐acylamides at GPR132.
SB‐583831 and SB‐583355 are peptidomimetic molecules containing core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. We describe pharmacological tools for GPR132, identified through drug screening. N‐linoleoylglycine and 9‐HODE also activate rat and mouse GPR132, despite limited sequence conservation to human. Physiological concentrations of N‐acylglycines in tissue are sufficient to activate GPR132. The order‐of‐potency is N‐palmitoylglycine > 9‐HODE ≈ N‐linoleoylglycine > linoleamide > N‐oleoylglycine ≈ N‐stereoylglycine > N‐arachidonoylglycine > N‐docosehexanoylglycine. Here, we identify N‐acylamides in particular N‐acylglycines, as lipid activators of GPR132 with comparable activity to 9‐HODE. Other suggested GPR132 agonists including lysophosphatidylcholine (LPC) have not been readily reproduced. The G‐protein‐coupled receptor GPR132, also known as G2A, is activated by 9‐hydroxyoctadecadienoic acid (9‐HODE) and other oxidized fatty acids.
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