Xie Qiong, Wang Hao, Xia Zheng, Lu Meiyan, Zhang Weiwei, Wang Xinghai, Fu Wei, Tang Yun, Sheng Wei, Li Wei, Zhou Wei, Zhu Xu, Qiu Zhuibai, Chen Hongzhuan
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai, P. R. China.
J Med Chem. 2008 Apr 10;51(7):2027-36. doi: 10.1021/jm070154q. Epub 2008 Mar 12.
Bis-(-)-nor-meptazinols (bis-(-)-nor-MEPs) 5 were designed and synthesized by connecting two (-)-nor-MEP monomers with alkylene linkers of different lengths via the secondary amino groups. Their acetylcholinesterase (AChE) inhibitory activities were more greatly influenced by the length of the alkylene chain than butyrylcholinesterase (BChE) inhibition. The most potent nonamethylene-tethered dimer 5h exhibited low-nanomolar IC 50 values for both ChEs, having a 10 000-fold and 1500-fold increase in inhibition of AChE and BChE compared with (-)-MEP. Molecular docking elucidated that 5h simultaneously bound to the catalytic and peripheral sites in AChE via hydrophobic interactions with Trp86 and Trp286. In comparison, it folded in the large aliphatic cavity of BChE because of the absence of peripheral site and the enlargement of the active site. Furthermore, 5h and 5i markedly prevented the AChE-induced Abeta aggregation with IC 50 values of 16.6 and 5.8 microM, similar to that of propidium (IC 50 = 12.8 microM), which suggests promising disease-modifying agents for the treatment of AD patients.
通过仲氨基将两个(-)-去甲美普他醇单体与不同长度的亚烷基连接基相连，设计并合成了双(-)-去甲美普他醇(bis-(-)-nor-MEPs)5。与丁酰胆碱酯酶(BChE)抑制作用相比，它们的乙酰胆碱酯酶(AChE)抑制活性受亚烷基链长度的影响更大。最有效的壬亚甲基连接的二聚体5h对两种胆碱酯酶均表现出低纳摩尔的IC50值，与(-)-美普他醇相比，对AChE和BChE的抑制作用分别增加了10000倍和1500倍。分子对接表明，5h通过与Trp86和Trp286的疏水相互作用同时结合到AChE的催化位点和外周位点。相比之下，由于缺乏外周位点和活性位点的扩大，它在BChE的大脂肪族腔中折叠。此外，5h和5i显著抑制AChE诱导的Aβ聚集，IC50值分别为16.6和5.8μM，与碘化丙啶(IC50 = 12.8μM)相似，这表明它们有望成为治疗AD患者的疾病修饰药物。
