cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

doi:10.1111/febs.13260

Paper

cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

Published Aug 1, 2015 · Thomas Malcomson, K. Yelekçi, M. T. Borrello

The FEBS Journal

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28

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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 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.

In Vitro Study

Study Snapshot

Cyclopropylamines with cis-positions show potential as selective MAO B inhibitors without inhibiting LSD1.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

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References

Citations

Rearrangement, Elimination, and Ring-Opening Reactions of Cyclopropyl-Substituted Nitrenium Ions: A Computational and Experimental Investigation.

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