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

Gerard Esteban, Jennifer Allan, Abdelouahid Samadi, Andrea Mattevi, Mercedes Unzeta, José Marco-Contelles, Claudia Binda, Rona R. Ramsay

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

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 × 106 min- 1 M- 1) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor.

Original languageEnglish
Pages (from-to)1104-1110
Number of pages7
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1844
Issue number6
DOIs
Publication statusPublished - Jun 2014
Externally publishedYes

Keywords

  • ASS234
  • Alzheimer's disease
  • Crystal structure
  • Flavin adduct
  • Multi-target drug
  • PF9601N

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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