Fluorinated phenylcyclopropylamines. Part 5: Effects of electron-withdrawing or -donating aryl substituents on the inhibition of monoamine oxidases A and B by 2-aryl-2-fluoro-cyclopropylamines.
A series of racemic, diastereoisomeric aryl cyclopropylamines substituted with fluorine in the 2-position and electron-donating and electron-withdrawing groups on the aromatic ring have been prepared. These represent analogues of the classic MAO inhibitor tranylcypromine (trans-2-phenylcyclopropylamine, 1). Their activities as inhibitors of recombinant human liver monoamine oxidases A (MAO A) and B (MAO B) were determined. The trans-compounds were low micromolar inhibitors of both MAO A and MAO B with moderate MAO A selectivity while the less active cis-analogues were MAO B selective. In the trans-series, electron-withdrawing para-substituents increased the potency of MAO A inhibition while electron-donating groups such as methyl or methoxy had no influence on this activity. In contrast, aromatic ring substitution in the trans-series had essentially no effect on the inhibition of MAO B. The corresponding cis-compounds were shown to be 10-100 times less active against MAO A, while trans- and cis-compounds were quite similar in terms of inhibition of MAO B. The best MAO A/MAO B selectivity (7:1) in the trans-series was found for trans-2-fluoro-2-(para-trifluoromethylphenyl)cyclopropylamine (7d), while a 1:27 selectivity was found for cis-2-fluoro-2-(para-fluorophenyl)cyclopropylamine (10c). These results are discussed in connection with the pK(a) and logD values, the mechanism of action of tranylcypromines, and the geometry of the active site of the enzymes.
Hruschka
Svenja
S
Organisch-Chemisches Institut and International NRW Graduate School of Chemistry, Universität Münster, Corrensstr. 40, D-48149 Münster, Germany.
Rosen
Thomas C
TC
Yoshida
Shinichi
S
Kirk
Kenneth L
KL
Fröhlich
Roland
R
Wibbeling
Birgit
B
Haufe
Günter
G
D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology*; D004583:Electrons; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D008958:Models, Molecular; D008967:Molecular Biology; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D003521:Cyclopropanes; D008996:Monoamine Oxidase Inhibitors; D005461:Fluorine