Medicinal Chemistry Research, Lundbeck Research Denmark, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
J Med Chem. 2010 Sep 9;53(17):6386-97. doi: 10.1021/jm100697g.
The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
描述了一系列变构毒蕈碱 M(1)受体激动剂的发现和构效关系(SAR)。基于其对毒蕈碱 M(1)受体的高选择性，化合物 17（Lu AE51090）被鉴定为该系列中的代表性化合物，作为毒蕈碱 M(1)受体激动剂，在一系列毒蕈碱受体亚型中均具有高选择性。此外，17 在广泛的 G 蛋白偶联受体、离子通道、转运体和酶的测试中表现出高度的选择性，并且在啮齿动物中具有可接受的药代动力学特征和足够的脑暴露，以便在体内对化合物进行表征。因此，在学习和记忆的啮齿动物模型中，17 逆转了延迟诱导的自然遗忘，表明 17 具有潜在的认知促进作用。
