1. Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease.
- Author
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Toda N, Tago K, Marumoto S, Takami K, Ori M, Yamada N, Koyama K, Naruto S, Abe K, Yamazaki R, Hara T, Aoyagi A, Abe Y, Kaneko T, and Kogen H
- Subjects
- Alzheimer Disease metabolism, Animals, Carrier Proteins metabolism, Cholinesterase Inhibitors pharmacology, Cholinesterase Inhibitors therapeutic use, Dose-Response Relationship, Drug, Membrane Glycoproteins metabolism, Mice, Rats, Serotonin Plasma Membrane Transport Proteins, Structure-Activity Relationship, Acetylcholinesterase metabolism, Alzheimer Disease drug therapy, Carrier Proteins antagonists & inhibitors, Cholinesterase Inhibitors chemical synthesis, Drug Design, Membrane Glycoproteins antagonists & inhibitors, Membrane Transport Proteins, Nerve Tissue Proteins
- 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.
- Published
- 2003
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