Fluorinated phenylcyclopropylamines. Part 3: Inhibition of monoamine oxidase A and B

Bioorg Med Chem. 2004 May 15;12(10):2645-52. doi: 10.1016/j.bmc.2004.03.010.

Abstract

Fluorinated phenylcyclopropylamines and alkylamines were examined as inhibitors of recombinant human liver monoamine oxidase A (MAO A) and B (MAO B). For a series of trans- and cis-2-fluoro-2-phenylcyclopropylamine analogues, the presence of fluorine attached to a cyclopropane ring was found to result in an increase in inhibitory activity towards both MAO A and B. In addition, p-substitution of electron-withdrawing groups such as Cl and F in the aromatic ring of the trans-isomers increased the inhibition of both enzymes. (1S,2S)-2-Fluoro-2-phenylcyclopropylamine was a more potent inhibitor of both MAO A and B than was the (1R,2R)-enantiomer, indicating that the presence of fluorine has no influence on the enantioselectivity of MAO inhibition, since a similar effect of stereochemistry has been reported for tranylcypromine. Interestingly, fluorination at the 2-position of 1-phenycyclopropylamine, which is known as a selective inhibitor of MAO B relative to MAO A, reversed the selectivity and resulted in a potent inhibitor selective for MAO A. All inhibitors showed time- and concentration-dependent inhibition for both enzymes, with the exception of trans-2-fluoro-2-phenylcyclopropyl ethylamine, which acts as a competitive and reversible MAO A selective inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fluorine / chemistry*
  • Humans
  • Liver / enzymology
  • Molecular Structure
  • Monoamine Oxidase / drug effects*
  • Monoamine Oxidase Inhibitors / chemistry*
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Tranylcypromine / analogs & derivatives*
  • Tranylcypromine / chemistry
  • Tranylcypromine / pharmacology

Substances

  • 2-fluoro-2-phenylcyclopropylamine
  • Monoamine Oxidase Inhibitors
  • Fluorine
  • Tranylcypromine
  • Monoamine Oxidase