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 treatment of depression and can�cer. 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 determined from docking experiments 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. For reversible inhibition, most compounds gave high
IC50 values with MAO A, but sub-micromolar values with MAO B. After
pre-incubation of the cyclopropylamine with the enzyme, the inhibition was
irreversible for both MAO A and MAO B, and the activity was not restored
by dilution. Spectral changes during inactivation of MAO A included
bleaching at 456 nm and an increased absorbance at 400 nm, consistent with
flavin modification. These derivatives are MAO B-selective irreversible inhib�itors that do not show inhibition of LSD1. The best inhibitor was cis-N-ben�zyl-2-methoxycyclopropylamine, with an IC50 of 5 nM for MAO B and
170 nM for MAO A after 30 min pre-incubation. This cis-cyclopropylamine
is over 20-fold more effective than tranylcypromine, so may be studied as a
lead for selective inhibitors of MAO B that do not inhibit LSD1.