Messer W S, Abuh Y F, Liu Y, Periyasamy S, Ngur D O, Edgar M A, El-Assadi A A, Sbeih S, Dunbar P G, Roknich S, Rho T, Fang Z, Ojo B, Zhang H, Huzl J J, Nagy P I
Department of Medicinal & Biological Chemistry, College of Pharmacy, The University of Toledo, Ohio 43606, USA.
J Med Chem. 1997 Apr 11;40(8):1230-46. doi: 10.1021/jm960467d.
Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.
先前的研究鉴定出了几种在大鼠脑中表现出毒蕈碱激动剂活性的新型四氢嘧啶衍生物。这类化合物可能有助于治疗与乙酰胆碱水平低下相关的认知和记忆缺陷，如在阿尔茨海默病中所见。为了确定对毒蕈碱受体亚型的结合和活性重要的配体分子特征，扩展了四氢嘧啶系列。通过使用细胞系中表达的受体亚型对毒蕈碱受体活性进行生化研究，进一步检测了几种活性化合物的功能选择性。几种脒衍生物在A9 L细胞中对与磷酸肌醇（PI）代谢偶联的m1受体显示出高效能，而对m3受体的活性较低。包括1b、1f、2b和7b在内的四种配体对m1受体与m3受体表现出明显的功能选择性。化合物1f在A9 L细胞中对与腺苷酸环化酶抑制偶联的m2受体也表现出低活性。还启动了分子模拟研究，以使用m1受体的九个氨基酸模型来帮助理解毒蕈碱激动剂与m1受体相互作用的性质。确定了几种重要的相互作用，包括酯部分与Thr192之间的相互作用。还发现恶二唑和炔基衍生物与Asn382有额外的相互作用，这表明通过最大化与Asp105、Thr192和Asn382的相互作用可能实现增强的效力和选择性。综上所述，数据表明几种脒衍生物对m1毒蕈碱受体表现出功能选择性，值得作为治疗阿尔茨海默病的治疗剂进行进一步评估。此外，确定了几个氨基酸残基作为m1激动剂的潜在结合位点。这些数据可能有助于指导开发更具选择性的m1激动剂的努力。
