1. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.
- Author
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Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, and Reynet C
- Subjects
- Animals, Appetite Depressants administration & dosage, Appetite Depressants chemistry, Cyclic AMP metabolism, Diet, Dose-Response Relationship, Drug, Endocannabinoids, Humans, Male, Mice, Molecular Sequence Data, Obesity drug therapy, Oleic Acids administration & dosage, Oleic Acids chemistry, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled genetics, Substrate Specificity, Time Factors, Yeasts metabolism, Appetite Depressants pharmacology, Feeding Behavior drug effects, Oleic Acids metabolism, Oleic Acids pharmacology, Receptors, G-Protein-Coupled metabolism
- 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.
- Published
- 2006
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