Kinetics, mechanism, and inhibition of monoamine oxidase

Abstract

Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital antidepressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help to maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer's disease, albeit not yet proven clinically. Vital information for inhibitor design comes from an understanding of the structure, mechanism, and kinetics of the catalyst. This review will summarize the kinetic behaviour of MAO A and B and the kinetic evaluation of reversible inhibitors that transiently decrease catalysis. Kinetic parameters and crystal structures have enabled computational approaches to ligand discovery and validation of hits by docking. Kinetics and a wide variety of substrates and inhibitors along with theoretical modelling have also contributed to proposed schemes for the still debated chemical mechanism of amine oxidation. However, most of the marketed MAO drugs are long-lasting irreversible inactivators. The mechanism of irreversible inhibition by hydrazine, cyclopropylamine, and propargylamine drugs will be discussed. The article finishes with some examples of the propargylamine moiety in multi-target ligand design to combat neurodegeneration.

Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

“…Given that each profile consisted of 10 distinct trajectories, corresponding to different initial inhibitor configurations, we can safely state that all performed simulations were well-converged and pointed to consistent conclusions. The calculated activation free energies of Δ G ‡ (RAS) = 27.6 and Δ G ‡ (SEL) = 24.5 kcal mol −1 indicated a higher reactivity of SEL, being in excellent agreement with the determined k inact values of 0.99 min −1 for SEL [ 71 ] and 0.0533 min −1 for RAS [ 72 ]. Even more so, these experimental parameters translated to a difference in the activation free energy of 1.7 kcal mol −1 in favor of SEL, which was nicely matched by our calculations of ΔΔ G ‡ = 3.1 kcal mol −1 here, thus lending to a strong credence to the presented results.…”

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

“…Consequently, inhibitors of both enzymes are established in the pharmacotherapy for neurological diseases. [1][2][3] Moclobemide was the first marketed MAO inhibitor and entered the Swedish market in 1989. 4 Slowing down the degradation of neurotransmitters like dopamine and norepinephrine via MAO A inhibition, this drug exhibits moodlifting properties facilitating its use as an antidepressant.…”

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

“…They share up to 70% identical sequences, but have different affinities for neurotransmitters. MAO-A selectively catabolizes dopamine, serotonin (5-hydroxytryptamine, 5-HT), and norepinephrine, while MAO-B catabolizes dopamine, phenethylamine, and benzylamine [3]. Inhibition of MAO-A is a common strategy to increase the concentration of 5-HT in the synaptic cleft, whereas acute systemic injection of a MAO inhibitor induces inhibition of 5-HT cell firing [1].…”