title: Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease.
abstract: We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration.
authors.affiliation: Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
authors.forename: Narihiro
authors.initials: N
authors.lastname: Toda
authors.forename: Keiko
authors.initials: K
authors.lastname: Tago
authors.forename: Shinji
authors.initials: S
authors.lastname: Marumoto
authors.forename: Kazuko
authors.initials: K
authors.lastname: Takami
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ori
authors.forename: Naho
authors.initials: N
authors.lastname: Yamada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Koyama
authors.forename: Shunji
authors.initials: S
authors.lastname: Naruto
authors.forename: Kazumi
authors.initials: K
authors.lastname: Abe
authors.forename: Reina
authors.initials: R
authors.lastname: Yamazaki
authors.forename: Takao
authors.initials: T
authors.lastname: Hara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Aoyagi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Abe
authors.forename: Tsugio
authors.initials: T
authors.lastname: Kaneko
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kogen
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D002800:Cholinesterase Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D000110:Acetylcholinesterase