Development Of Monoamine Oxidase Inhibitors Research Articles

Serendipity in psychotropic drugs: Unearthing the origins

This is a dive into the history of several groundbreaking psychiatric drugs and their discoveries. The article begins by exploring the curious origin of the word “serendipity” following Horace Walpole’s encounter with a fairytale. This captivating emergence of “serendipity” is followed by an account of lithium discovered in 1817. About a century and a half later, lithium would receive FDA approval, becoming a cornerstone in the treatment of mania.The narrative meanders to other drugs that have a similar thread of serendipity woven into their beginnings— chlordiazepoxide, meprobamate, chlorpromazine, finally halting at iproniazid, an anti-tubercular agent that unexpectedly revealed its mood-enhancing potential and paved the way for the development of monoamine oxidase inhibitors as antidepressants.The authors navigate through the intricacies of chance and discovery that have influenced the trajectory of psychiatric drug development, leading to unexpected breakthroughs that have forever left their mark on the undeniably vast landscape that is mental health.

Enzyme Inhibition Assays for Monoamine Oxidase.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines with two isoforms, namely, MAO-A and MAO-B, in mitochondrial outer membranes. These two types of MAO-A and MAO-B participate in changes in levels of neurotransmitter such as serotonin (5-hydroxytryptamine) and dopamine. Selective MAO-A inhibitors have been targeted for anti-depression treatment, while selective MAO-B inhibitors are targets of therapeutic agents for Alzheimer's disease and Parkinson's disease. For this reason, study on the development of MAO inhibitors has recently become important. Here, we describe methods of MAO activity assay, especially continuous spectrophotometric methods, which give relatively high accuracy. MAO-A and MAO-B can be assayed using kynuramine and benzylamine as substrates, respectively, at 316nm and 250nm, respectively, to measure their respective products, 4-hydroxyquinoline and benzaldehyde. Inhibition degree and pattern can be analyzed by using the Lineweaver-Burk and secondary plots in the presence of inhibitor, and reversibility of inhibitor can be determined by using the dialysis method.

Navigating into the Chemical Space of Monoamine Oxidase Inhibitors by Artificial Intelligence and Cheminformatics Approach.

The monoamine oxidase (MAO) enzyme class is a prevalent target for many neurodegenerative and depressive disorders. Even though scrutinization of many promising drugs for the treatment of MAO inhibition has been carried out in recent times, a conclusive structural requirement for potent activity needs to be developed. Numerous approaches have been examined for the identification of structural features for potent MAO inhibitors (MAOIs) that mainly involve an array of computational studies, synthetic approaches, and biological evaluation. In this paper, we have analyzed ∼2200 well-known MAOIs to expand perceptions in the chemical space of MAOIs. The physicochemical properties of the MAOIs disclosed a discernible hydrophobic feature making a bunch discrete from the central nervous system (CNS) acting drugs, as exposed using the principal component analysis (PCA). The Murcko scaffold structure study revealed unfavorable and favorable scaffold structures, in both data sets, with the highest biological activity shown by the 3-phenyl-2H-chromen-2-one scaffold. This scaffold showed a polypharmacological effect. R-group disintegration and automatic structure–activity relationship (SAR) study resulted in identification of substructures responsible for the inhibitory bioactivity of the MAO-A and MAO-B enzymes. Moreover, with activity cliff analysis, significant biological activity was detected by simple molecular conversion in the chemical compound structure. In addition, we used the machine learning tool to generate a hypothesis wherein pyrazole, benzene ring, and amide containing structural functionalities can exhibit potential biological activities. This hypothesis revealed that CNS target drugs, C4155, C13390, C21265, C43862, C31524, C24810, C37100, C42075, and C43644, could be repurposed as valuable candidates for the MAO-B enzyme. For researchers, this study will bring new perceptions in the discovery and development of MAOIs and direct lead and hit optimization for the progress of small molecules beneficial for MAO-targeting associated diseases.

Quantitative Structure-Activity Relationship (QSAR) Studies for the Inhibition of MAOs.

Monoamine oxidases are the crucial drug targets for the treatment of neurodegenerative disorders like depression, Parkinson's disease, and Alzheimer's disease. The enzymes catalyze the oxidative deamination of several monoamine containing neurotransmitters, i.e. serotonin (5-HT), melatonin, epinephrine, norepinephrine, phenylethylamine, benzylamine, dopamine, tyramine, etc. The oxidative reaction of monoamine oxidases results in the production of hydrogen peroxide that leads to the neurodegeneration process. Therefore, the inhibition of monoamine oxidases has shown a profound effect against neurodegenerative diseases. At present, the design and development of newer lead molecules for the inhibition of monoamine oxidases are under intensive research in the field of medicinal chemistry. Recently, the advancement in QSAR methodologies has shown considerable interest in the development of monoamine oxidase inhibitors. The present review describes the development of QSAR methodologies, and their role in the design of newer monoamine oxidase inhibitors. It will assist the medicinal chemist in the identification of selective and potent monoamine oxidase inhibitors from various chemical scaffolds.

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors.

Background:Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer’s, and Parkinson’s Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing.Methods:Major depressive episode (MDE) subjects underwent [11C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine.Results:Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300–600mg daily (n = 11), 83.75±5.52% for moclobemide at 900–1200mg daily (n = 9), and 86.82±6.89% for phenelzine at 45–60mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean ‘a’: 88.62±2.38%, mean ‘b’: 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45–60mg) and higher-dose moclobemide (900–1200mg) compared to lower-dose moclobemide [300–600mg; F(7,16) = 3.94, p = 0.01].Conclusions:These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300–600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

Early Development of Monoamine Oxidase Inhibitors

This article reviews the history of monoamine oxidase inhibitors (MAOIs) from their initial synthesis in the early 1900s until the present. The recognition of their potential psychiatric benefits came when the only available effective treatment for depressed patients was seizure therapy. The introduction of medications to treat depressive illness heralded an exciting new era of psychopharmacology; however, reports of paroxysmal hypertensive crises dampened enthusiasm. Dietary restrictions and drug interactions with MAOIs are now defined, but apprehension and a lack of familiarity cause infrequent prescribing of MAOIs despite their powerful effect across a wide range of psychiatric disorders. As demonstrated at Columbia University’s Depression Evaluation Service, founded in 1977 by the late Frederic M. Quitkin, MD, MAOIs remain effective agents that should be considered for depressed or anxious patients who have not improved sufficiently following at least one prior treatment attempt with a different class of medication. The use of moclobemide and the selegiline transdermal system as primary treatments requires clarification. [ Psychiatr Ann . 2014;44(12):563–566.]

Chromone, a Privileged Scaffold for the Development of Monoamine Oxidase Inhibitors

Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of γ-pyrone nucleus act preferably as MAO-B inhibitors, with IC(50) values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of γ-pyrone nucleus result in complete loss of activity in both isoforms (chromones 2-12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC(50) of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives.

Recent development of monoamine oxidase inhibitors

The monoamine oxidases (MAO-A and MAO-B) are flavoenzymes located in the outer mitochondrial membrane responsible for the oxidative deamination of many endogenous and exogenous monoamines. Recognition of the importance of monoamine oxidases as targets for drug intervention for the treatment of a variety of conditions, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and other psychiatric and neurological disorders, has produced an enormous interest in the development of molecules that act as inhibitors on these enzymes. This review mainly focuses on the numerous monoamine oxidase inhibitor (MAO-I)-related patents published from August 2002 to June 2005. In this paper recent developments of monoamine oxidase inhibitors are reported, ordering all patents by molecular structure. A structure–activity relationship (SAR) study that reports on known MAO inhibitors is also outlined before a discussion on new associations with other drugs of classical MAO inhibitors and their new target.

Lasker Award: Priority Claim

To the Editor:— I want to protest officially the recognition that has been accorded Dr. Nathan S. Kline's role in the development of monoamine oxidase inhibitors, and specifically iproniazid, for the treatment of depression. This matter becomes currently urgent because of Dr. Kline's recent acceptance of the Lasker Award and the publication inThe Journalof his paper The Practical Management of Depression, presented as a result of this ( 190 :732 [Nov 23] 1964). Neither the terms of the award nor the paper recognize that my role was primary in the development and administration of this drug for this purpose. There can be no doubt that intellectual dishonesty is involved here. I am enclosing a substantiating reprint (Saunders, J.C.: Treatment of Hospitalized Depressed and Schizophrenic Patients With Monoamine Oxidase Inhibitors: Including Reflections on Pargyline, Ann NY Acad Sci 107 :1081 [July 8] 1963) and a copy of my letter of