cis-Cyclopropylamines as mechanism-based inhibitors of Monoamine Oxidases

Abstract

Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for the therapy of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity from docking revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. The reversible inhibition of MAO A gave high IC50 values for most compounds but sub-micromolar values with MAO B. After pre-incubation with the enzyme, the inhibition was irreversible in both MAO A and MAO B and the activity was not restored by dilution. Spectral changes during inactivation of MAO A showed bleaching at 456 nm and an increase at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective mechanism-based inhibitors without inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5 nM for MAO B and 170 nM for MAO A after 30 min preincubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine so could be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1.