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Bioorganic & Medicinal Chemistry Sep 2023Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO...
Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.
Topics: Humans; Male; Antidepressive Agents; Brain; Caco-2 Cells; Clorgyline; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Prostatic Neoplasms
PubMed: 37544256
DOI: 10.1016/j.bmc.2023.117425 -
The Medical Letter on Drugs and... Aug 2023
Topics: Humans; Anxiety Disorders
PubMed: 37516898
DOI: 10.58347/tml.2023.1682a -
Reviews in Medical Virology Sep 2023Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems... (Review)
Review
Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems through catalytic oxidation and deamination. MAO dysfunction is closely related to human neurological and psychiatric diseases and cancers. However, little is known about the relationship between MAO and viral infections in humans. This review summarises current research on how viral infections participate in the occurrence and development of human diseases through MAO. The viruses discussed in this review include hepatitis C virus, dengue virus, severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, Japanese encephalitis virus, Epstein-Barr virus, and human papillomavirus. This review also describes the effects of MAO inhibitors such as phenelzine, clorgyline, selegiline, M-30, and isatin on viral infectious diseases. This information will not only help us to better understand the role of MAO in the pathogenesis of viruses but will also provide new insights into the treatment and diagnosis of these viral diseases.
Topics: Humans; Monoamine Oxidase; Epstein-Barr Virus Infections; COVID-19; Herpesvirus 4, Human; Monoamine Oxidase Inhibitors
PubMed: 37294534
DOI: 10.1002/rmv.2465 -
Drug and Chemical Toxicology Jan 2024Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized...
Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized for treatment. The purpose of this study was to evaluate the effect and mechanisms of phenelzine, an FDA-approved antidepressant, on APAP-induced toxicity in HepG2 cells. The human liver hepatocellular cell line HepG2 was used to investigate APAP-induced cytotoxicity. The protective effects of phenelzine were determined by examining the cell viability, combination index calculation, Caspase 3/7 activation, Cytochrome c release, HO levels, NO levels, GSH activity, PERK protein levels, and pathway enrichment analysis. Elevated HO production and decreased glutathione (GSH) levels were indicators of APAP-induced oxidative stress. The combination index of 2.04 indicated that phenelzine had an antagonistic effect on APAP-induced toxicity. When compared to APAP alone, phenelzine treatment considerably reduced caspase 3/7 activation, cytochrome c release, and HO generation. However, phenelzine had minimal effect on NO and GSH levels and did not alleviate ER stress. Pathway enrichment analysis revealed a potential connection between APAP toxicity and phenelzine metabolism. These findings suggested that phenelzine's protective effect against APAP-induced cytotoxicity could be attributed to the drug's capacity to reduce APAP-mediated apoptotic signaling.
Topics: Humans; Acetaminophen; Hep G2 Cells; Phenelzine; Caspase 3; Cytochromes c; Hydrogen Peroxide; Liver; Oxidative Stress; Apoptosis; Chemical and Drug Induced Liver Injury; Glutathione
PubMed: 37246945
DOI: 10.1080/01480545.2023.2217696 -
Burns : Journal of the International... Apr 2024To observe depressive-like behavior and hippocampus monoamine oxidase A (MAOA) changes in burned mice.
OBJECTIVE
To observe depressive-like behavior and hippocampus monoamine oxidase A (MAOA) changes in burned mice.
METHODS
We tested depression and anxiety like behaviors of burn C57 mice with the sucrose preference test, forced swimming test (FST), open field test and elevated plus maze test and then detected the MAOA content and MAOA gene transcriptional levels in the hippocampus with western blot analysis and real-time quantitative PCR analysis. We then sought to reverse depressive-like behavior of burned mice with an MAOA inhibitor.
RESULTS
(1) Mice showed depressive and anxiety like behaviors one week after they were burned; (2) The content of MAOA in the hippocampus of burned mice was significantly higher than that in control mice (P<0.05); (3) MAOA gene transcription in the hippocampus of burned mice was significantly increased (MAOA mRNA was increased, P<0.05); (4) treatment with a MAOA inhibitor (phenelzine) significantly increased the sucrose preference rate and decreased FST immobility time in burned mice, and also decreased elevated expression of MAOA in the hippocampus of burned mice.
CONCLUSION
Burned mice showed "delayed" depressive-like behavior combined with a degree of anxiety; this phenomenon is likely associated with the increase in MAOA expression in the hippocampus.
Topics: Animals; Mice; Burns; Depression; Disease Models, Animal; Hippocampus; Monoamine Oxidase; Stress, Psychological; Sucrose; Up-Regulation
PubMed: 28413107
DOI: 10.1016/j.burns.2017.03.013