cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

Abstract

Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysinespecific 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 IC 50 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.

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…Malcomson et al described the inhibition of MAO‐B by selected cis isomers of primary and secondary cyclopropylamines with an alkoxy group at the position 2 of cyclopropyl ring (compounds 59a ‐ h ; Figure ). The IC 50 values of compounds 59a , 59b , 59d , and 59e were found to be in micromolar range for MAO‐B, demonstrating that the selectivity of reversible binding for MAO‐B was as good as the standard drug tranylcypromine (TCP; 59h ) for 59c , 59f , and 59g , or better than TCP ( 59h ) for 59a , 59b , 59d , and 59e .…”

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs<strong> </strong>

“…Many other new series of compounds have been Cyclopropylamines Tranylcypromine (Parnate), which was introduced in the 1960s, inactivates MAO, with a slight preference for MAO B, but it inhibits MAO A in the gut sufficiently well in vivo to cause a hypertensive crisis unless dietary restrictions are followed [53]. Cyclopropylamines have been studied as inactivators of MAO [54][55][56] and of the epigentic-modifying flavoenzyme, enzyme LSD-1 [57]. Tranylcypromine ( Figure 1a) also inhibits the copper-containing amine oxidases [58] and cytochrome P450 isoforms [59,60].…”

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

“…For medicinal chemistry screening, irreversible inhibition can be detected as a decrease in the IC 50 value after 30 min preincubation compared to no preincubation. For example, for MAO B the IC50 for tranylcypromine without preincubation is 4 μM but if preincubated with the enzyme for 30 min before substrate is added, the IC 50 is 0.074 μM (Malcomson et al, 2015). Proper characterization of mechanism-based inactivation requires measurement of the rate of production of inactive enzyme over time with several inhibitor concentrations to obtain K I and k inact (Kitz and Wilson, 1962).…”

“…The propargyl group must be oxidized by MAO to generate the reactive species that forms the covalent bond with the enzyme. The rate of inactivation by propargyl compounds for both MAO A and MAO B is around 0.2 min −1 with selectivity coming from the binding (Esteban et al, 2014; Malcomson et al, 2015). A further benefit of the propargyl moiety is its association with neuroprotection at levels lower than for inhibition of MAO (Naoi and Maruyama, 2010; Weinreb et al, 2011).…”