Fluorinated phenylcyclopropylamines. Part 4: effects of aryl substituents and stereochemistry on the inhibition of monoamine oxidases by 1-aryl-2-fluoro-cyclopropylamines.
A series of para-ring-substituted (E)- and (Z)-1-aryl-2-fluorocyclopropylamines were examined as inhibitors of recombinant human liver monoamine oxidase A (MAO A) and B (MAO B). Unlike the parent 1-phenylcyclopropylamine, which is a selective inhibitor of MAO B, both (E)- and (Z)-diastereomers of derivatives having fluorine at the 2-position of the cyclopropane ring were potent and selective irreversible inhibitors of MAO A. Both electron releasing groups (Me, OMe) and electron attracting groups (Cl, F) substituted in the para-position caused a modest increase in activity. Geminal difluoro-substitution caused a loss of potency of 100-fold compared to either (E)- or (Z)-monofluorinated analogue. Surprisingly, (1S,2R)-2-fluoro-1-phenylcyclopropylamine and the (1R,2S)-enantiomer were essential equally potent as inhibitors of MAO A and MAO B. None of the tested 1-aryl-2-fluorocyclopropylamines exhibited significant inhibition of tyramine oxidase.
Ye
Song
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.
Yoshida
Shinichi
S
Fröhlich
Roland
R
Haufe
Günter
G
Kirk
Kenneth L
KL
D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003521:Cyclopropanes; D008996:Monoamine Oxidase Inhibitors; C067351:cyclopropylamine; D008995:Monoamine Oxidase