N ‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132

We describe pharmacological tools for GPR132, identified through drug screening. SKF‐95667 is a novel GPR132 agonist. SB‐583831 and SB‐583355 are peptidomimetic molecules contai ning core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. A telmisartan analog, GSK1820795A, antagonizes the actions ofN‐acylamides at GPR132. The synthetic cannabinoid CP‐55 940 also activates GPR132. 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. Small‐molecule ligands are envisaged to occupy a “classical” site encapsulated in the 7TM bundle. Structure‐directed mutagenesis indicates a critical role for arginine at position 203 in transmembrane domain 5 to mediate GPR132 activation byN‐acylamides. Our data suggest distinct modes of binding for small‐molecule and lipid agonists to the GPR132 receptor. Antagonists, such as those described here, will be vital to understand the physiological role of this long‐studied target.

Source: Pharmacology Research and Perspectives - November 20, 2019 Category: Drugs & Pharmacology Authors: James R. Foster, Shohta Ueno, Mao Xiang Chen, Jenni Harvey, Simon J. Dowell, Andrew J. Irving, Andrew J. Brown Tags: ORIGINAL ARTICLE Source Type: research