Transformation of Heterocyclic Reversible Monoamine Oxidase-B Inactivators into Irreversible Inactivators by N-Methylation

Charles Z. Ding, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

3-[4-[(3-Chlorophenyl)methoxy]phenyl]-5-[(methylamino)methyl]-2-oxazolidinone (1) is a secondary amine known to be a potent time-dependent irreversible inactivator of monoamine oxidase B (MAO-B). The primary amine analogues of derivatives of 1, as well as of the corresponding dihydrofuranone and pyrrolidinone, had been shown to be time-dependent, but reversible, inhibitors of MAO-B. Here it is shown that the primary amine analogue of 1 is a time-dependent reversible inhibitor of MAO-B and that the secondary and tertiary amine analogues of the corresponding oxazolidinone, dihydrofuranone, and pyrrolidinone are time-dependent irreversible inhibitors of MAO-B. The reaction leading to the irreversible enzyme adduct formation with 1 can be reversed by increasing the temperature. These results are consistent with a stabilizing stereoelectronic effect on the enzyme adduct caused by N-methylation which hinders free rotation and prevents the sp3-orbital containing the nitrogen nonbonded electrons from being trans to the active site amino acid leaving group.

Original languageEnglish (US)
Pages (from-to)3606-3610
Number of pages5
JournalJournal of Medicinal Chemistry
Volume36
Issue number23
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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