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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

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Author(s)

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

School/Research organisations

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.
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Details

Original languageEnglish
Pages (from-to)1104–1110
Number of pages6
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1844
Issue number6
Early online date16 Mar 2014
DOIs
StatePublished - Jun 2014
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    Research areas

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

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