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Chemico-biological Interactions May 2019Phenelzine (β-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important... (Review)
Review
Phenelzine (β-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important pharmacological properties which may alter the effects of oxidative stress. After conducting a comprehensive literature search, the authors of this review paper aim to provide an overview and discussion of the mechanisms by which phenelzine may attenuate oxidative stress. It inhibits γ-aminobutyric acid (GABA) transaminase, resulting in elevated brain GABA levels, inhibits both MAO and primary amine oxidase and, due to its hydrazine-containing structure, reacts chemically to sequester a number of reactive aldehydes (e.g. acrolein and 4-hydroxy-2-nonenal) proposed to be implicated in oxidative stress in a number of neurodegenerative disorders. Phenelzine is unusual in that it is both an inhibitor of and a substrate for MAO, the latter action producing at least one active metabolite, β-phenylethylidenehydrazine (PEH). This metabolite inhibits GABA transaminase, is a very weak inhibitor of MAO but a strong inhibitor of primary amine oxidase, and sequesters aldehydes. Phenelzine may ameliorate the effects of oxidative stress by reducing formation of reactive metabolites (aldehydes, hydrogen peroxide, ammonia/ammonia derivatives) produced by the interaction of MAO with biogenic amines, by sequestering various other reactive aldehydes and by inhibiting primary amine oxidase. In PC12 cells treated with the neurotoxin MPP, phenelzine has been reported to reduce several adverse effects of MPP. It has also been reported to reduce lipid peroxidative damage induced in plasma and platelet proteins by peroxynitrite. In animal models, phenelzine has a neuroprotective effect in global ischemia and in cortical impact traumatic brain injury. Recent studies reported in the literature on the possible involvement of acrolein in spinal cord injury and multiple sclerosis indicate that phenelzine can attenuate adverse effects of acrolein in these models. Results from studies in our laboratories on effects of phenelzine and PEH on primary amine oxidase (which catalyzes formation of toxic aldehydes and is overexpressed in Alzheimer's disease), on sequestration of the toxic aldehyde acrolein, and on reduction of acrolein-induced toxicity in mouse cortical neurons are also reported.
Topics: Animals; Antidepressive Agents; Free Radical Scavengers; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oxidative Stress; Phenelzine
PubMed: 30857888
DOI: 10.1016/j.cbi.2019.03.003 -
Journal of Microbiology and... Jul 2021Three compounds were isolated from marine-derived sp. CNQ-031, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE),...
Three compounds were isolated from marine-derived sp. CNQ-031, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) were evaluated. Compound 1 (5,7-dihydroxy-2-isopropyl-4H-chromen-4-one) was a potent and selective inhibitor of MAO-A, with a 50% inhibitory concentration (IC) of 2.70 μM and a selectivity index (SI) of 10.0 versus MAO-B. Compound 2 [5,7-dihydroxy-2-(1-methylpropyl)-4H-chromen-4-one] was a potent and low-selective inhibitor of MAO-B, with an IC of 3.42 μM and an SI value of 2.02 versus MAO-A. Compound 3 (1-methoxyphenazine) did not inhibit MAO-A or MAO-B. All three compounds showed little inhibitory activity against AChE, BChE, and BACE-1. The K value of compound 1 for MAO-A was 0.94 ± 0.28 μM, and the K values of compound 2 for MAO-A and MAO-B were 3.57 ± 0.60 and 1.89 ± 0.014 μM, respectively, with competitive inhibition. The 1-methylpropyl group in compound 2 increased the MAO-B inhibitory activity compared with the isopropyl group in compound 1. Inhibition of MAO-A and MAO-B by compounds 1 and 2 was recovered by dialysis experiments. These results suggest that compounds 1 and 2 are reversible, competitive inhibitors of MAOs and can be considered potential therapies for neurological disorders such as depression and Alzheimer's disease.
Topics: Animals; Chromones; Geologic Sediments; Humans; Inhibitory Concentration 50; Kinetics; Molecular Structure; Monoamine Oxidase Inhibitors; Seawater; Streptomyces
PubMed: 34099598
DOI: 10.4014/jmb.2105.05003 -
British Medical Journal (Clinical... Mar 1982
Topics: Humans; Male; Monoamine Oxidase Inhibitors; Oligospermia; Sperm Count; Spermatogenesis; Sulfasalazine
PubMed: 6121603
DOI: 10.1136/bmj.284.6319.844 -
European Journal of Medicinal Chemistry Mar 2024Monoamine oxidases A and B (MAO A, B) are ubiquitous enzymes responsible for oxidative deamination of amine neurotransmitters and xenobiotics. Despite decades of... (Review)
Review
Monoamine oxidases A and B (MAO A, B) are ubiquitous enzymes responsible for oxidative deamination of amine neurotransmitters and xenobiotics. Despite decades of studies, MAO inhibitors (MAOIs) find today limited therapeutic space as second-line drugs for the treatment of depression and Parkinson's disease. In recent years, a renewed interest in MAOIs has been raised up by several studies investigating the role of MAOs, particularly MAO A, in tumor insurgence and progression, and the efficacy of MAOIs as coadjutants in the therapy of chemoresistant tumors. In this survey, we highlight the implication of MAOs in the biochemical pathways of tumorigenesis and review the state-of-the-art of preclinical and clinical studies of MAOIs as anticancer agents used in monotherapy or in combination with antitumor chemotherapeutics.
Topics: Humans; Monoamine Oxidase Inhibitors; Monoamine Oxidase; Parkinson Disease
PubMed: 38290352
DOI: 10.1016/j.ejmech.2024.116180 -
Molecules (Basel, Switzerland) Mar 2023Monoamine oxidase (MAO) oxidizes neurotransmitters and xenobiotic amines, including vasopressor and neurotoxic amines such as the MPTP neurotoxin. Its inhibitors are...
Monoamine oxidase (MAO) oxidizes neurotransmitters and xenobiotic amines, including vasopressor and neurotoxic amines such as the MPTP neurotoxin. Its inhibitors are useful as antidepressants and neuroprotectants. This work shows that diluted soy sauce (1/3) and soy sauce extracts inhibited human MAO-A and -B isozymes in vitro, which were measured with a chromatographic assay to avoid interferences, and it suggests the presence of MAO inhibitors. Chromatographic and spectrometric studies showed the occurrence of the β-carboline alkaloids harman and norharman in soy sauce extracts inhibiting MAO-A. Harman was isolated from soy sauce, and it was a potent and competitive inhibitor of MAO-A (0.4 µM, 44 % inhibition). The concentrations of harman and norharman were determined in commercial soy sauces, reaching 243 and 52 μg/L, respectively. Subsequently, the alkaloids 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (THCA) and 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) were identified and analyzed in soy sauces reaching concentrations of 69 and 448 mg/L, respectively. The results show that MTCA was a precursor of harman under oxidative and heating conditions, and soy sauces increased the amount of harman under those conditions. This work shows that soy sauce contains bioactive β-carbolines and constitutes a dietary source of MAO-A and -B inhibitors.
Topics: Humans; Soy Foods; Carbolines; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Alkaloids; Plant Extracts; Amines
PubMed: 36985694
DOI: 10.3390/molecules28062723 -
International Journal of Molecular... Jan 2023Parkinson's disease (PD) is the second most common neurodegenerative disease in older individuals worldwide. Pharmacological treatment for such a disease consists of...
Parkinson's disease (PD) is the second most common neurodegenerative disease in older individuals worldwide. Pharmacological treatment for such a disease consists of drugs such as monoamine oxidase B (MAO-B) inhibitors to increase dopamine concentration in the brain. However, such drugs have adverse reactions that limit their use for extended periods; thus, the design of less toxic and more efficient compounds may be explored. In this context, cheminformatics and computational chemistry have recently contributed to developing new drugs and the search for new therapeutic targets. Therefore, through a data-driven approach, we used cheminformatic tools to find and optimize novel compounds with pharmacological activity against MAO-B for treating PD. First, we retrieved from the literature 3316 original articles published between 2015-2021 that experimentally tested 215 natural compounds against PD. From such compounds, we built a pharmacological network that showed rosmarinic acid, chrysin, naringenin, and cordycepin as the most connected nodes of the network. From such compounds, we performed fingerprinting analysis and developed evolutionary libraries to obtain novel derived structures. We filtered these compounds through a docking test against MAO-B and obtained five derived compounds with higher affinity and lead likeness potential. Then we evaluated its antioxidant and pharmacokinetic potential through a docking analysis (NADPH oxidase and CYP450) and physiologically-based pharmacokinetic (PBPK modeling). Interestingly, only one compound showed dual activity (antioxidant and MAO-B inhibitors) and pharmacokinetic potential to be considered a possible candidate for PD treatment and further experimental analysis.
Topics: Humans; Aged; Parkinson Disease; Monoamine Oxidase Inhibitors; Structure-Activity Relationship; Neurodegenerative Diseases; Antioxidants; Monoamine Oxidase
PubMed: 36674652
DOI: 10.3390/ijms24021134 -
CNS Drugs Aug 2021(Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous...
Cardiovascular Effects of Combining Subcutaneous or Intravenous Esketamine and the MAO Inhibitor Tranylcypromine for the Treatment of Depression: A Retrospective Cohort Study.
BACKGROUND
(Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous administration is currently not recommended because of concern about hypertensive crises.
OBJECTIVE
Our objective was to evaluate whether changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during esketamine administration differed between patients who concomitantly received tranylcypromine and those who did not.
METHODS
This was a retrospective cohort study utilizing cardiovascular monitoring data from inpatients treated for severe depression in unipolar, bipolar, and schizoaffective disorder. Primary outcomes were change in mean BP and HR during the first hour after intravenous or subcutaneous esketamine administration compared with baseline, controlled for confounders. Secondary analyses quantify differences in absolute BP during esketamine treatment and comparisons of BP peaks, temporal effects, and intraindividual comparisons before and after tranylcypromine initiation.
RESULTS
Our analysis included 509 esketamine administrations in 43 patients, 14 of whom concomitantly received tranylcypromine. Controlling for creatinine and age, mean ± standard deviation (SD) BP changes were significantly increased by concomitant tranylcypromine treatment (ΔSBP: F[1,503] = 86.73, p < 0.001; ΔDBP: F[1,503] = 55.71, p < 0.001), but HR remained unaffected. Mean SBP change during esketamine administration was 2.96 ± 18.11 mmHg in patients receiving tranylcypromine (TCP+) and -8.84 ± 11.31 mmHg in those who did not (TCP-). Changes in DBP were -2.81 ± 11.20 mmHg for TCP+ and -10.77 ± 9.13 mmHg for TCP-. Moreover, we found a significant dose-response relationship between tranylcypromine dose and BP (SBP: B = 0.35, standard error [SE] = 0.12, 95% confidence interval [CI] 0.12-0.60, p = 0.004; adjusted R = 0.11, p = 0.008; DBP: B = 0.21, SE = 0.08, 95% CI 0.06-0.36, p = 0.007; adjusted R = 0.08; p = 0.023).
CONCLUSIONS
Although statistically significant changes in BP were identified in patients receiving tranylcypromine and esketamine, these changes were clinically insignificant. Thus, combining esketamine and this MAOI appears to be safe at standard doses. The dose-response relationship calls for caution with higher doses of tranylcypromine.
Topics: Administration, Intravenous; Adult; Aged; Antidepressive Agents; Blood Pressure; Cohort Studies; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Dose-Response Relationship, Drug; Drug Interactions; Female; Heart Rate; Humans; Injections, Subcutaneous; Ketamine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Retrospective Studies; Tranylcypromine; Young Adult
PubMed: 34283390
DOI: 10.1007/s40263-021-00837-6 -
European Journal of Nuclear Medicine... Sep 2022[F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer's disease biomarkers, including aggregated neurofibrillary tau (NFT)...
PURPOSE
[F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer's disease biomarkers, including aggregated neurofibrillary tau (NFT) with [F]flortaucipir. Due to structural similarities of flortaucipir with some monoamine oxidase A (MAO-A) inhibitors, this study aimed to evaluate flortaucipir binding to MAO-A and MAO-B and any potential impact on PET interpretation.
METHODS
[F]Flortaucipir autoradiography was performed on frozen human brain tissue slices, and PET imaging was conducted in rats. Dissociation constants were determined by saturation binding, association and dissociation rates were measured by kinetic binding experiments, and IC values were determined by competition binding.
RESULTS
Under stringent wash conditions, specific [F]flortaucipir binding was observed on tau NFT-rich Alzheimer's disease tissue and not control tissue. In vivo PET experiments in rats revealed no evidence of [F]flortaucipir binding to MAO-A; pre-treatment with MAO inhibitor pargyline did not impact uptake or wash-out of [F]flortaucipir. [F]Flortaucipir bound with low nanomolar affinity to human MAO-A in a microsomal preparation in vitro but with a fast dissociation rate relative to MAO-A ligand fluoroethyl-harmol, consistent with no observed in vivo binding in rats of [F]flortaucipir to MAO-A. Direct binding of flortaucipir to human MAO-B was not detected in a microsomal preparation. A high concentration of flortaucipir (IC of 1.3 μM) was found to block binding of the MAO-B ligand safinamide to MAO-B on microsomes suggesting that, at micromolar concentrations, flortaucipir weakly binds to MAO-B in vitro.
CONCLUSION
These data suggest neither MAO-A nor MAO-B binding will contribute significantly to the PET signal in cortical target areas relevant to the interpretation of [F]flortaucipir.
Topics: Alzheimer Disease; Animals; Brain; Carbolines; Humans; Ligands; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Positron-Emission Tomography; Rats; tau Proteins
PubMed: 35596745
DOI: 10.1007/s00259-022-05822-9 -
Molecules (Basel, Switzerland) Jun 2022Sixteen compounds () were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and...
Sixteen compounds () were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound was the most potent inhibitor against MAO-B with an IC value of 0.17 μM, followed by (IC = 0.27 μM). and selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the -chloro substituent in and increased the inhibitory activity of MAO-B. and were reversible MAO-B inhibitors that were competitive, with K values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, respectively. The PAMPA method indicated that compounds and had the tendency to traverse the blood-brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.
Topics: Dopamine Agents; Kinetics; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 35744926
DOI: 10.3390/molecules27123801 -
Journal of Nuclear Medicine : Official... Feb 2016The aim of this study was to radiolabel a novel bis-deuterium substituted l-deprenyl analog (fluorodeprenyl-D2) with (18)F and to evaluate its potential to visualize and...
UNLABELLED
The aim of this study was to radiolabel a novel bis-deuterium substituted l-deprenyl analog (fluorodeprenyl-D2) with (18)F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo.
METHODS
The precursor compound ( 5A: + 5B: ) and reference standard ( 6: ) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with (18)F-fluorodeprenyl-D2. A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography.
RESULTS
The 50% inhibitory concentration of compound 6 for MAO-B was 227 ± 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of (18)F-fluorodeprenyl-D2 was consistent with known MAO-B expression in the human brain. In vivo, (18)F-fluorodeprenyl-D2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time-activity curves were better described by the 2-tissue-compartment model. Administration of a 1 mg/kg dose of l-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. (18)F-fluorodeprenyl-D2 showed less irreversibility than did previously reported MAO-B radioligands.
CONCLUSION
The results suggest that (18)F-fluorodeprenyl-D2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.
Topics: Animals; Autoradiography; Blood Proteins; Carbon Radioisotopes; Fluorine Radioisotopes; Humans; Isotope Labeling; Macaca fascicularis; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Radiopharmaceuticals; Recombinant Proteins; Selegiline
PubMed: 26585057
DOI: 10.2967/jnumed.115.161083