Monoamine Oxidase Inhibitors: From Classic to New Clinical Approaches

Monoamine oxidases (MAOs) are involved in the oxidative deamination of different amines and neurotransmitters. This pointed them as potential targets for several disorders and along the last 70 years a wide variety of MAO inhibitors have been developed as successful drugs for the treatment of complex diseases, being the first drugs approved for depression in the late 1950s. The discovery of two MAO isozymes (MAO-A and B) with different substrate selectivity and tissue expression patterns led to novel therapeutic approaches and to the development of new classes of inhibitors, such as selective irreversible and reversible MAO-B inhibitors and reversible MAO-A inhibitors. Significantly, MAO-B inhibitors constitute a widely studied group of compounds, some of them approved for the treatment of Parkinson's disease. Further applications are under development for the treatment of Alzheimer's disease, amyotrophic lateral sclerosis, and cardiovascular diseases, among others. This review summarizes the most important aspects regarding the development and clinical use of MAO inhibitors, going through mechanistic and structural details, new indications, and future perspectives. Monoamine oxidases (MAOs) catalyze the oxidative deamination of different amines and neurotransmitters. The two different isozymes, MAO-A and MAO-B, are located at the outer mitochondrial membrane in different tissues. The enzymatic reaction involves formation of the corresponding aldehyde and releasing hydrogen peroxide (H₂O₂) and ammonia or a substituted amine depending on the substrate. MAO's role in neurotransmitter metabolism made them targets for major depression and Parkinson's disease, among other neurodegenerative diseases. Currently, these compounds are being studied for other diseases such as cardiovascular ones.