title: Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice.
abstract: Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder which is characterized by the progressive deterioration of cognition and the emergence of behavioral and psychological symptoms in aging patients. Given that the clinical effectiveness of acetylcholinesterase inhibitors (AChEIs) has still been questioned due to dubious disease-modifying effects, the multi-target directed ligand (MTDL) design has become an emerging strategy for developing new drugs for AD treatment. Bis(9)-(-)-nor-meptazinol (Bis-Mep) was firstly reported by us as a novel MTDL for both potent cholinesterase and amyloid-β aggregation inhibition. In this study, we further explored its AChE inhibition kinetic features and cognitive amelioration. Bis-Mep was found to be a mixed-type inhibitor on electric eel AChE by enzyme kinetic study. Molecular docking revealed that two "water bridges" located at the two wings of Bis-Mep stabilized its interaction with both catalytic and peripheral anionic sites of AChE. Furthermore, subcutaneous administration of Bis-Mep (10, 100 or 1000 ng/kg) significantly reversed the scopolamine-induced memory deficits in a typical bell-shaped dose-response manner. The maximal cognitive amelioration of Bis-Mep was achieved at 100 ng/kg, comparable with the effect of a reference drug Huperzine A at 1 mg/kg and also the relevant AChE inhibition in brain. These findings suggested that Bis-Mep might be a promising dual-binding AChE inhibitor for potential AD therapeutics.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Zhang
authors.forename: Jian-rong
authors.initials: JR
authors.lastname: Xu
authors.forename: Xin-Xing
authors.initials: XX
authors.lastname: Ge
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Cui
authors.forename: Zhui-Bai
authors.initials: ZB
authors.lastname: Qiu
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000470:Alkaloids / Q000008:administration & dosage; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000523:psychology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D008621:Meptazinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D018697:Nootropic Agents / Q000737:chemistry / Q000494:pharmacology*; D012601:Scopolamine / Q000633:toxicity*; D012717:Sesquiterpenes / Q000008:administration & dosage
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D012717:Sesquiterpenes; C583419:bis(9)-normeptazinol; C050426:huperzine A; D008621:Meptazinol; D012601:Scopolamine; D000110:Acetylcholinesterase