Abstract
Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / pharmacology
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Animals
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Binding Sites
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Butyrylcholinesterase / chemistry*
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Butyrylcholinesterase / metabolism
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Cell Survival / drug effects
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Cholinesterase Inhibitors / chemistry*
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Cholinesterase Inhibitors / metabolism
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Cholinesterase Inhibitors / pharmacology
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Cholinesterase Inhibitors / therapeutic use
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Cognitive Dysfunction / drug therapy
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Cognitive Dysfunction / pathology
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Disease Models, Animal
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Drug Design
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Ghrelin / metabolism
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Half-Life
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Humans
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Mice
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Mice, Inbred ICR
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Molecular Dynamics Simulation
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Neuroprotective Agents / chemistry*
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Peptide Fragments / pharmacology
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Quinolines / chemistry
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Quinolines / metabolism
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Quinolines / pharmacology
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Quinolines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Up-Regulation / drug effects
Substances
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Amyloid beta-Peptides
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Cholinesterase Inhibitors
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Ghrelin
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Neuroprotective Agents
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Peptide Fragments
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Quinolines
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amyloid beta-protein (1-42)
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Butyrylcholinesterase