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cis ‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases
Author(s) -
Malcomson Thomas,
Yelekci Kemal,
Borrello Maria Teresa,
Ganesan A.,
Semina Elena,
De Kimpe Norbert,
Mangelinckx Sven,
Ramsay Rona R.
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13260
Subject(s) - chemistry , tranylcypromine , substituent , stereochemistry , monoamine oxidase , enzyme , ic50 , biochemistry , in vitro
Cyclopropylamines, inhibitors of monoamine oxidases ( MAO ) and lysine‐specific demethylase ( LSD 1), provide a useful structural scaffold for the design of mechanism‐based inhibitors for treatment 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 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 LSD 1 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 inhibitors that do not show inhibition of LSD 1. The best inhibitor was cis‐N ‐benzyl‐2‐methoxycyclopropylamine, with an IC 50 of 5 n m for MAO B and 170 n m 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 LSD 1.