Ojo B, Dunbar P G, Durant G J, Nagy P I, Huzl J J, Periyasamy S, Ngur D O, el-Assadi A A, Hoss W P, Messer W S
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, OH 43606, USA.
Bioorg Med Chem. 1996 Oct;4(10):1605-15. doi: 10.1016/0968-0896(96)00152-6.
As part of a continuing effort aimed at the development of selective, efficacious, and centrally active m1 muscarinic agonists for the treatment of Alzheimer's disease, a series of amide and hydrazide amidine derivatives (2a-e and 3b-d) was synthesized and examined for muscarinic agonist activity. Preliminary biochemical studies indicated that 2b, 2d, and 3d bound to muscarinic receptors in rat brain and stimulated phosphoinositide (PI) metabolism in rat cerebral cortex. Compounds 2b and 2d were also highly efficacious at m1 muscarinic receptors expressed in cultured A9 L cells. Molecular modeling studies suggest slightly different modes of interaction with m1 receptors for the ester and amide derivatives. Also, hydrogen-bond formation with a Thr residue may be important for m1 muscarinic agonist potency. The data suggest that the amide moiety can replace the ester group found in muscarinic agonists and provide further support for the utility of amidine derivatives in the development of efficacious m1 agonists.
作为致力于开发用于治疗阿尔茨海默病的选择性、高效且具有中枢活性的M1毒蕈碱激动剂的持续努力的一部分，合成了一系列酰胺和酰肼脒衍生物（2a - e和3b - d），并检测其毒蕈碱激动剂活性。初步生化研究表明，2b、2d和3d与大鼠脑中的毒蕈碱受体结合，并刺激大鼠大脑皮层中的磷酸肌醇（PI）代谢。化合物2b和2d在培养的A9 L细胞中表达的M1毒蕈碱受体上也具有高效性。分子模拟研究表明，酯和酰胺衍生物与M1受体的相互作用模式略有不同。此外，与苏氨酸残基形成氢键可能对M1毒蕈碱激动剂的效力很重要。数据表明，酰胺部分可以取代毒蕈碱激动剂中的酯基，并为脒衍生物在开发高效M1激动剂中的应用提供进一步支持。
