Aliphatic Propargylamines: Potent, Selective, Irreversible Monoamine Oxidase B Inhibitors

J Med Chem. 1992 Oct 2;35(20):3705-13. doi: 10.1021/jm00098a017.

Abstract

A series of aliphatic propargylamine derivatives has been synthesized. Some of them possess highly potent, irreversible, selective, inhibitory activity toward monoamine oxidase B (MAO-B). The potency of the inhibitors is related to chain length and substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO inhibitory activity as assessed in vitro increased as the aliphatic carbon chain length increased. Substitution of a hydrogen by hydroxyl, carboxyl, or carbethoxyl groups at the aliphatic chain terminal or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced the inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent than those with longer chains in inhibiting brain MAO-B activity in vivo especially after oral administration. Chronic administration of low doses of the aliphatic propargylamines caused a slight cumulative inhibition of MAO-A activity in the mouse brain. These MAO-B inhibitors appear to be nontoxic, and they do not possess an amphetamine-like moiety in their structure as is the case for deprenyl. We expect that these aliphatic propargylamines may be useful in the treatment in certain neuropsychiatric disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Liver / drug effects
  • Liver / enzymology
  • Mice
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Pargyline / analogs & derivatives*
  • Propylamines / chemical synthesis*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Monoamine Oxidase Inhibitors
  • Propylamines
  • Pargyline
  • Monoamine Oxidase