Abstract
Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/KI=3×10(6) min(-1)M(-1)) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor.
Keywords:
ASS234; Alzheimer’s disease; Crystal structure; Flavin adduct; Multi-target drug; PF9601N.
Copyright © 2014 Elsevier B.V. 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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Butyrylcholinesterase / chemistry
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Clorgyline / chemistry
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Donepezil
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Flavin-Adenine Dinucleotide / chemistry
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Humans
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Indans / chemistry
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Indoles / chemistry*
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Kinetics
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Models, Molecular
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Monoamine Oxidase / chemistry*
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Monoamine Oxidase / metabolism
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Monoamine Oxidase Inhibitors / chemistry*
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Neuroprotective Agents / chemistry*
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Piperidines / chemistry*
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
Substances
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Indans
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Indoles
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Monoamine Oxidase Inhibitors
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N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine
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Neuroprotective Agents
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Piperidines
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Recombinant Proteins
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Flavin-Adenine Dinucleotide
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Donepezil
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Monoamine Oxidase
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Acetylcholinesterase
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Butyrylcholinesterase
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Clorgyline