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

Graphic 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2004-05, Vol.12 (10), p.2645-2652
Main Authors: Yoshida, Shinichi, Rosen, Thomas C, Meyer, Oliver G.J, Sloan, Milton J, Ye, Song, Haufe, Günter, Kirk, Kenneth L
Format: Article
Language:English
Subjects:
Biological and medical sciences
Flavin
Fluorinated phenylcyclopropylamine
Fluorine - chemistry
Humans
Inhibitor
Liver - enzymology
Medical sciences
Miscellaneous
Molecular Structure
Monoamine oxidase
Monoamine Oxidase - drug effects
Monoamine Oxidase Inhibitors - chemistry
Monoamine Oxidase Inhibitors - pharmacology
Pharmacology. Drug treatments
Tranylcypromine - analogs & derivatives
Tranylcypromine - chemistry
Tranylcypromine - pharmacology
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Summary:Graphic 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. (1 S,2 S)-2-Fluoro-2-phenylcyclopropylamine was a more potent inhibitor of both MAO A and B than was the (1 R,2 R)-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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2004.03.010