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 pKa and log D values, the mechanism of action of tranylcypromines, and the geometry of the active site of the enzymes.

Electron-withdrawing para-substituents increase the potency of MAO A inhibition in the trans-series, while electron-donating groups have a weak influence on this activity. In contrast, aromatic ring substitution has essentially no effect on inhibition of MAO B. The corresponding cis-compounds are 10–100 times less active.Figure optionsDownload as PowerPoint slide