Fluorinated phenylcyclopropylamines. Part 3: Inhibition of monoamine oxidase A and B.
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.
Yoshida
Shinichi
S
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. syoshida@pref.tottori.jp
Rosen
Thomas C
TC
Meyer
Oliver G J
OG
Sloan
Milton J
MJ
Ye
Song
S
Haufe
Günter
G
Kirk
Kenneth L
KL
D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
C484867:2-fluoro-2-phenylcyclopropylamine; D008996:Monoamine Oxidase Inhibitors; D005461:Fluorine; D014191:Tranylcypromine; D008995:Monoamine Oxidase