Institut de Recherches Internationales Servier, 92284 Suresnes, France.
Genepep SA, 34430 Saint Jean de Vedas, France.
Molecules. 2021 Feb 27;26(5):1291. doi: 10.3390/molecules26051291.
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.
黑色素浓缩激素（MCH）是一种在动物（包括鱼类、两栖类和哺乳动物）脑中发现的 19 个氨基酸长的肽。MCH 参与食欲和/或能量平衡。其受体（MCH-R1）的拮抗剂可能是理解 MCH 作用机制和对抗肥胖综合征的主要工具（或最终药物），肥胖综合征是一个全球性的社会健康问题。自从 MCH 受体的去孤儿化以来，我们克隆、表达并表征了受体 MCH-R1，并开始了一项广泛的药物化学计划，旨在发现这种可用的化合物。在本最终工作中，我们描述了 GPS18169，这是一种 MCH-R1 受体的假肽拮抗剂，其亲和力在纳摩尔范围内，其拮抗作用的 Ki 值在 20 皮摩尔范围内。与最初的母体化合物 S38151 相比，其代谢稳定性得到了相当的改善。我们在高脂肪饮食的小鼠体内实验中对其进行了测试。GPS18169 被发现能够有效限制脂肪组织的积累，并且，我们观察到治疗动物的胰岛素水平正常化，而食物或水的消耗没有变化。
