TY - JOUR

T1 - cis-Cyclopropylamines as mechanism-based inhibitors of monoamine oxidases

AU - Malcomson, Thomas

AU - Yelekci, Kemal

AU - Borrello, Maria Teresa

AU - Ganesan, A

AU - Semina, Elena

AU - De Kimpe, Norbert

AU - Mangelinckx, Sven

AU - Ramsay, Rona R

N1 - © 2015 FEBS.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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 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 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 inhibitors that do not show 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 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.

AB - 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 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 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 inhibitors that do not show 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 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.

KW - Antidepressive Agents/chemistry

KW - Catalytic Domain

KW - Cyclopropanes/chemistry

KW - Histone Demethylases/antagonists & inhibitors

KW - Humans

KW - In Vitro Techniques

KW - Kinetics

KW - Models, Molecular

KW - Monoamine Oxidase/chemistry

KW - Monoamine Oxidase Inhibitors/chemistry

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Tranylcypromine/chemistry

U2 - 10.1111/febs.13260

DO - 10.1111/febs.13260

M3 - Journal article

C2 - 25755053

VL - 282

SP - 3190

EP - 3198

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

IS - 16

ER -