Transformation of Monoamine Oxidase-B Primary Amine Substrates into Time-Dependent Inhibitors. Tertiary Amine Homologues of Primary Amine Substrates

Charles Z. Ding, Xingliang Lu, Kuniko Nishimura, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

A family of N-methylated and N,N-dimethylated alkyl and arylalkylamines was prepared and more than half of the analogues were shown to be time-dependent pseudo-first-order inhibitors of monoamine oxidase-B. Some of the time-dependent inactivators were reversible and others were irreversible with respect to prolonged dialysis following inactivation. Partition ratios ranged from zero to 11 000. These results are rationalized in terms of a combination of an inductive effect and a stereoelectronic effect as a result of hindered rotation of an active site covalent adduct. A molecular mechanics calculation indicates that there is at least 10 kcal/mol of torsional energy to be overcome in order for the enzyme adduct to be released. These findings show that tertiary amine homologues of primary amine substrates of monoamine oxidase are time-dependent inhibitors, and this should be useful in the design of new inactivators of this enzyme.

Original languageEnglish (US)
Pages (from-to)1711-1715
Number of pages5
JournalJournal of Medicinal Chemistry
Volume36
Issue number12
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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