title: Bis-(-)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-beta aggregation.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai, P. R. China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Meiyan
authors.initials: M
authors.lastname: Lu
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xinghai
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Wei
authors.initials: W
authors.lastname: Sheng
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Xu
authors.initials: X
authors.lastname: Zhu
authors.forename: Zhuibai
authors.initials: Z
authors.lastname: Qiu
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects*; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008621:Meptazinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D008621:Meptazinol; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase