Abstract
Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression.
Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / chemistry*
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Acetylcholinesterase / metabolism*
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / epidemiology
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Amino Acid Motifs
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / metabolism
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Catalytic Domain*
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / pharmacology
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Cholinesterase Inhibitors / therapeutic use
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Donepezil
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Drug Discovery
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Humans
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Indans / chemistry
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Indans / pharmacology
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Indans / therapeutic use
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Models, Molecular
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Piperidines / chemistry
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Protein Multimerization / drug effects
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Protein Structure, Quaternary
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Quinolines / chemistry
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Quinolines / pharmacology
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Quinolines / therapeutic use
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Tacrine / chemistry*
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Tacrine / pharmacology*
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Tacrine / therapeutic use
Substances
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Amyloid beta-Peptides
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Cholinesterase Inhibitors
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Indans
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Piperidines
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Quinolines
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Tacrine
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Donepezil
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quinoline
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Acetylcholinesterase
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human