title: Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.
abstract: Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC5031.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ42) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP695cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.affiliation: b Department of Pharmacology , Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , Shanghai , P. R. China.
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: b Department of Pharmacology , Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , Shanghai , P. R. China.
authors.forename: Biyun
authors.initials: B
authors.lastname: Shao
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.affiliation: b Department of Pharmacology , Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , Shanghai , P. R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.|c NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research , Shanghai , P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: b Department of Pharmacology , Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , Shanghai , P. R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sheng
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: b Department of Pharmacology , Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , Shanghai , P. R. China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.affiliation: b Department of Pharmacology , Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , Shanghai , P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Department of Medicinal Chemistry , School of Pharmacy, Fudan University , Shanghai , P. R. China.
authors.forename: Zhuibai
authors.initials: Z
authors.lastname: Qiu
mesh_terms: D000682:Amyloid / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008621:Meptazinol / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000682:Amyloid; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D008621:Meptazinol; D002802:Cholinesterases
keywords: (−)-meptazinol; Pharmacophore; acetylcholinesterase; amyloidogenesis; carbamates