MCH-R1 Antagonist GPS18169, a Pseudopeptide,Is a Peripheral Anti-Obesity Agent in Mice |
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Authors: | Jean A. Boutin Magali Jullian Lukasz Frankiewicz Mathieu Galibert Philippe Gloanec Thierry Le Diguarher Philippe Dupuis Amber Ko Laurent Ripoll Marc Bertrand Anne Pecquery Gilles Ferry Karine Puget |
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Affiliation: | 1.Institut de Recherches Internationales Servier, 92284 Suresnes, France;2.Genepep SA, 34430 Saint Jean de Vedas, France; (M.J.); (L.F.); (M.G.); (K.P.);3.Institut de Recherches Servier, 92150 Suresnes, France;4.Technologie Servier, 45520 Gidy, France; (T.L.D.); (M.B.);5.Eurofins Discovery, 86600 Celle l’Evescault, France; (P.D.); (A.P.);6.Eurofins Discovery, New Taipei City 24891, Taiwan;7.Institut de Recherches Servier, 78290 Croissy-sur-Seine, France; |
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Abstract: | Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the brain of animals, including fishes, batrachians, and mammals. MCH is implicated in appetite and/or energy homeostasis. Antagonists at its receptor (MCH-R1) could be major tools (or ultimately drugs) to understand the mechanism of MCH action and to fight the obesity syndrome that is a worldwide societal health problem. Ever since the deorphanisation of the MCH receptor, we cloned, expressed, and characterized the receptor MCH-R1 and started a vast medicinal chemistry program aiming at the discovery of such usable compounds. In the present final work, we describe GPS18169, a pseudopeptide antagonist at the MCH-R1 receptor with an affinity in the nanomolar range and a Ki for its antagonistic effect in the 20 picomolar range. Its metabolic stability is rather ameliorated compared to its initial parent compound, the antagonist S38151. We tested it in an in vivo experiment using high diet mice. GPS18169 was found to be active in limiting the accumulation of adipose tissues and, correlatively, we observed a normalization of the insulin level in the treated animals, while no change in food or water consumption was observed. |
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Keywords: | diet-induced obesity MCH MCH-R1 antagonist pseudopeptide treatment |
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