Bis-(−)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-β Aggregation

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• 作者：Qiong Xie ; Hao Wang ; Zheng Xia ; Meiyan Lu ; Weiwei Zhang ; Xinghai Wang ; Wei Fu ; Yun Tang ; Wei Sheng ; Wei Li ; Wei Zhou ; Xu Zhu ; Zhuibai Qiu ; Hongzhuan Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 10, 2008
• 年：2008
• 卷：51
• 期：7
• 页码：2027 - 2036
• 全文大小：920K
• 年卷期：v.51,no.7(April 10, 2008)
• ISSN：1520-4804

文摘

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 IC₅₀ 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 Aβ aggregation with IC₅₀ values of 16.6 and 5.8 µM, similar to that of propidium (IC₅₀ = 12.8 µM), which suggests promising disease-modifying agents for the treatment of AD patients.