Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease

Biochim Biophys Acta. 2014 Jun;1844(6):1104-10. doi: 10.1016/j.bbapap.2014.03.006. Epub 2014 Mar 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Butyrylcholinesterase / chemistry
  • Clorgyline / chemistry
  • Donepezil
  • Flavin-Adenine Dinucleotide / chemistry
  • Humans
  • Indans / chemistry
  • Indoles / chemistry*
  • Kinetics
  • Models, Molecular
  • Monoamine Oxidase / chemistry*
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemistry*
  • Neuroprotective Agents / chemistry*
  • Piperidines / chemistry*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism

Substances

  • Indans
  • Indoles
  • Monoamine Oxidase Inhibitors
  • N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine
  • Neuroprotective Agents
  • Piperidines
  • Recombinant Proteins
  • Flavin-Adenine Dinucleotide
  • Donepezil
  • Monoamine Oxidase
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Clorgyline