New target for obesity and related metabolic disordersA new study reveals an attractive new target for therapies aimed at the treatment of obesity and related metabolic disorders, researchers report in the March Cell Metabolism. A novel compound, when delivered to rats on a high-fat diet, acted on the target receptor to suppress appetite and weight gain in the animals, they found.
As reported by Hilary Overton, Christine Reynet, and colleagues of the biotechnology company (OSI)Prosidion, the team found that so-called oleoylethanolamide, a naturally occurring lipid-signaling agent earlier shown to reduce food intake and weight gain in rats, can exert its effects through the G protein-coupled receptor (GPCR) GPR119. A large proportion of all drugs sold today target GPCRs, protein "switches" that recognize and translate signals into cellular responses. Found predominantly in the pancreas and digestive tract in humans and mice, as well as in the rodent brain, the function of GPR119 had previously remained mysterious.
After screening a proprietary library of small molecules including several hundred thousand compounds for their ability to activate GPR119, the researchers then identified one such chemical, known only as PSN632408. PSN632408 had no effect on the distantly related cannabinoid receptors, which are the targets of the candidate obesity drug rimonabant, the team reported.
PSN632408 led to a marked reduction in food intake in rats that took the compound orally, they reported. Total food intake over the first 24 hours was 10.4 percent lower in animals treated with 100 mg/kg PSN632408 than in control animals. Obese rats that were given PSN632408 everyday for two weeks also ate less and gained less weight and fat than those not taking the chemical.
"We think this might be quite a unique receptor for the treatment of obesity and other aspects of metabolic syndrome because of its localization in the gastrointestinal tract and its effect on fat mass," Reynet said. "We also have preliminary evidence for improvements on lipid profile and insulin sensitivity."
Further study found that PSN632408 and the prescribed weight-loss agent sibutramine similarly reduced food intake and weight gain in normal rats on a high-fat diet.
"Most of our studies suggest this prototypical compound might lead to reductions in body weight that can match the effects of sibutramine," added Jim McCormack, Vice President of Research for Prosidion Ltd. Sibutramine (Meridia®) is a marketed drug, although its use has been limited by its potential for side effects, including hypertension, McCormack noted. "While this is still the early days for understanding GPR119's function, the receptor offers potential for new agents for treating obesity and related metabolic disorders without the side effects."
Details of the mechanism by which such selective small molecules produce their effects remain to be elucidated, "but it is clear that this receptor system is a novel putative avenue for controlling caloric intake, body weight and some metabolic parameters, and hence has great potential value for discovering pharmaceuticals to alleviate the burdens of obesity and related metabolic disorders," the researchers said. The team said the search is on for additional compounds that might also act on GPR119.
Hilary A. Overton, Adam J. Babbs, Sheila M. Doel, Matthew C.T. Fyfe, Lisa S. Gardner, Martin J. Procter, Chrystelle M. Rasamison, Peter S. Widdowson, Geoffery M. Williams, and Christine Reynet of (OSI) Prosidion in Oxford, United Kingdom; Graeme Griffin of OSI Pharmaceuticals, Inc. in Farmingdale, New York; Helen C. Jackson of RenaSci Consultancy Limited in Nottingham, United Kingdom; Mads Tang-Christensen of Rheoscience A/S in Rødovre, Denmark.
Overton et al.: "Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents." Publishing in Cell Metabolism Vol. 3, 167–175, March 2006. DOI 10.1016/j.cmet.2006.02.004 www.cellmetabolism.org
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