文献类型：期刊文献

英文题名：Bis-(-)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-β aggregation

作者：Xie, Qiong[1];Wang, Hao[2];Xia, Zheng[2];Lu, Meiyan[1];Zhang, Weiwei[2];Wang, Xinghai[1];Fu, Wei[1];Tang, Yun[3];Sheng, Wei[1];Li, Wei[1];Zhou, Wei[2];Zhu, Xu[2];Qiu, Zhuibai[1];Chen, Hongzhuan[2]

机构：[1]Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 200032, Peoples R China;[2]Jiao Tong Univ, Sch Med, Inst Med Sci, Dept Pharmacol, Shanghai 200025, Peoples R China;[3]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China

年份：2008

卷号：51

期号：7

起止页码：2027

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000254709100008)】；

语种：英文

摘要：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 acetyleholinesterase (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-nano molar 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 A beta aggregation with IC50 values of 16.6 and 5.8 mu M, similar to that of propidium (IC50 = 12.8 mu M), which suggests promising disease-modifying agents for the treatment of AD patients.