Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents

Abstract

The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

“…Although perhaps not a direct agonist of cannabinoid receptors (Lambert et al, 1999), being a structural analogue of anandamide, OEA has cannabimimetic effects by competing with anandamide for the endocannabinoid-metabolizing enzyme, fatty acid amide hydrolase (Jonsson et al, 2001) and can be considered an ECL. OEA has recently been shown to be the endogenous ligand of an 'orphan' receptor GPR119, which appears to be localized primarily to gut-associated organs, with some CNS expression (Overton et al, 2006). OEA activity at the nuclear receptor PPARa has also been demonstrated recently; OEA was observed to regulate feeding behaviour and body weight and to induce lipolysis via PPARa-dependent mechanisms (Fu et al, 2003;Guzman et al, 2004).…”

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…The validity of this assertion is supported by the observation that, in common with cannabinoid receptors, GPR119 can bind certain fatty acid ethanolamides [81]. Identification of these molecules as potential ligands for GPR119 is significant since such compounds can negatively influence food intake, reduce visceral fat mass and lower body weight in various animal models of obesity [82][83][84].…”

“…In addition, steroyland palmitoyl-ethanolamide are also agonistic although the maximal response generated in a fluorescence-based assay in transfected yeast cells was lower with these ligands than with OEA [106]. Lysophospholipids may also be agonistic at GPR119 since a range of lysophosphatidycholine species having oleoly, steroyl or palmitoyl derivatives at the C-1 position were all able to raise cAMP in cells expressing GPR119; as were lysophosphatidylethanolamine and lysophosphatidylinositol [107].…”

A solid-phase method for the extraction and measurement of anandamide from multiple human biomatrices

“…The endocannabinoid, anandamide (N-arachidonoylethanolamine; AEA), is an endogenous, unsaturated fatty acid derivative that was first identified in porcine brain [1] and has since been characterised as a ligand for the cannabinoid receptors, CB1 and CB2 [2] and the orphan receptors GPR55 [3] and GPR119 [4]. AEA also binds to the Ca 2+ -dependent membrane transporter and vaniloid receptor 1 (TRPV1) [5].…”