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European Neuropsychopharmacology : the... Aug 2017It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been... (Review)
Review
It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: Part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and Part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. Pharmacological data of this review part I characterize TCP as an irreversible and nonselective MAO-A/B inhibitor at low therapeutic doses of 20mg/day with supplementary norepinephrine reuptake inhibition at higher doses of 40-60mg/day. Serotonin, norepinephrine, dopamine, and trace amines, such as the "endogenous amphetamine" phenylethylamine, are increased in brain, which leads to changes in neuroplasticity by e.g. increased neurotrophic growth factors and translates to reduced stress-induced hypersecretion of corticotropin releasing factor (CRF) and positive testing in animal studies of depression. TCP has a pharmacokinetic half-life (t) of only 2h which is considerably lower than for most other antidepressant drugs. However, a very long pharmacodynamic half-life of about one week is found because of the irreversible MAO inhibition. New studies show that, except for cytochrome P450 (CYP) 2A6, no other drug metabolizing CYP-enzymes are inhibited by TCP at therapeutic doses which defines a low potential of pharmacokinetic interactions in the direction from TCP to other drugs. Insufficient information is available, however, for plasma concentrations of TCP influenced by comedication. More quantitative data are also needed for TCP metabolites such as p-hydroxytranylcypromine and N-acetyltranylcypromine. Pharmacodynamic drug interactions comprise for instance severe serotonin toxicity (SST) with serotonergic drugs and hypertensive crisis with indirect sympathomimetics. Because of the risk of severe food interaction, TCP treatment remains beset with the need for a mandatory tyramine-restricted diet. Toxicity in overdose is similar to amitriptyline and imipramine according to the distance of therapeutic to toxic doses. In conclusion, TCP is characterized by an exceptional pharmacology which is different to most other antidepressant drugs, and a more special evaluation of clinical efficacy and safety may therefore be needed.
Topics: Animals; Depressive Disorder; Drug Interactions; Humans; Monoamine Oxidase Inhibitors; Tranylcypromine
PubMed: 28655495
DOI: 10.1016/j.euroneuro.2017.05.007 -
European Journal of Pharmacology Jan 2018We previously reported that 1,3-bisbenzylimidazolium (DBZIM) bromide was neuroprotective for the dopaminergic system in Parkinson's disease (PD) models of rodent,...
We previously reported that 1,3-bisbenzylimidazolium (DBZIM) bromide was neuroprotective for the dopaminergic system in Parkinson's disease (PD) models of rodent, however the underlying mechanism was unclear. We currently further confirmed that DBZIM ameliorated the Parkinsonian motor deficit and protected the nigrostriatal tract from the neurotoxicity of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH-MPTP) in C57Bl/6 mice. The dopaminergic degeneration in the substantia nigra par compacta (SNc) and striatum was analyzed by immunohistochemistry while the monoamine oxidase B (MAO-B) inhibition effect of DBZIM was determined by enzyme kinetics. DBZIM was at least as effective as the clinically approved anti-PD drug, l-deprenyl (Selegiline), for both neuroprotection and correction of motor deficits. Mechanistically, DBZIM inhibited the specific activity of MAO-B in the striatum and C6 cells without affecting the protein expression. DBZIM directly inhibited the enzymatic activity of a purified MAO-B protein with an estimated K value from 780 to 940nM, in par with that of l-deprenyl (970nM). The physical interaction between DBZIM and MAO-B was proven by NMR analysis, with K around 21.5-46.8μM. Our binding and modelling data further illustrated that DBZIM is a mixed inhibitor with its binding to active site partially hindering the substrate binding. Therefore, inhibiting MAO-B is a major mechanism through which DBZIM confers neuroprotection for the dopaminergic neurons against 2'-CH-MPTP toxicity. Remarkably, the post-lesion treatment with DBZIM provided greater anti-parkinsonian and neuroprotective effects than the l-deprenyl. The current study, together with our previous findings in a 6-OHDA PD model, demonstrated that DBZIM is a promising neuroprotectant for PD with anti-MAO-B property.
Topics: Animals; Binding Sites; Gene Expression Regulation, Enzymologic; Imidazoles; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Parkinsonian Disorders; Protein Conformation
PubMed: 29050969
DOI: 10.1016/j.ejphar.2017.10.023 -
Central Nervous System Agents in... 2016Despite the considerable interest in the search of new and potent human MAO inhibitors, an increasing number of research works deal with new therapeutic and analytical... (Review)
Review
Despite the considerable interest in the search of new and potent human MAO inhibitors, an increasing number of research works deal with new therapeutic and analytical approaches regarding these molecules. Our interest was focused on the detailed analysis of (i) new pharmacological options for selective hMAO inhibitors; (ii) innovative analytical procedures to discover/screen hMAO inhibitors, and (iii) the recent possibility of using labeled hMAO inhibitors to unravel neurodegenerative diseases and drug distribution. All these three aspects could open new scenarios stimulating the interest of researchers in this field.
Topics: Binding Sites; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroimaging; Structure-Activity Relationship
PubMed: 26320583
DOI: 10.2174/1871524915666150831141705 -
ACS Chemical Neuroscience Feb 2022()-(2-Methylpyrid-5-yl)-6-[(3-[F]fluoro-2-hydroxy)propoxy]quinoline ([F]SMBT-1) was recently developed as a novel class of selective and reversible monoamine oxidase-B...
()-(2-Methylpyrid-5-yl)-6-[(3-[F]fluoro-2-hydroxy)propoxy]quinoline ([F]SMBT-1) was recently developed as a novel class of selective and reversible monoamine oxidase-B (MAO-B) tracers for in vivo imaging of reactive astrogliosis via positron emission tomography. To investigate the effect of the chirality of [F]SMBT-1 on tracer performance, we synthesized ()-[F] ([F]SMBT-1) and ()-[F] and compared their binding properties, pharmacokinetics, and metabolism. ()- showed higher binding affinity to MAO-B and lower binding affinity to MAO-A than ()-, demonstrating a higher selectivity ratio (MAO-B/MAO-A). A pharmacokinetic study in mice demonstrated that both ()-[F] and ()-[F] showed sufficient initial brain uptake. However, ()-[F] was cleared significantly faster from the body. An abundant sulfoconjugate metabolite was observed in plasma for ()-[F] but not for ()-[F]. In vitro sulfation assays confirmed that ()- was more reactive than ()-, consistent with the in vivo findings. Mefenamic acid, a selective sulfotransferase 1A1 (SULT1A1) inhibitor, strongly inhibited the in vitro sulfation of ()- by mouse liver fractions, human liver cytosol fractions, and human recombinant SULT1A1 enzyme. Genetic polymorphisms of SULT1A1 did not affect the sulfation of ()- in vitro. In conclusion, ()-[F] had a more favorable binding affinity and binding selectivity for MAO-B than ()-[F]. Additionally, ()-[F] also possessed better pharmacological and metabolic properties than ()-[F]. These results suggest that ()-[F] ([F]SMBT-1) is a promising candidate for application in the imaging of MAO-B in vivo.
Topics: Animals; Brain; Gliosis; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Positron-Emission Tomography
PubMed: 35049267
DOI: 10.1021/acschemneuro.1c00655 -
Molecules (Basel, Switzerland) Dec 2020The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO,...
The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The K values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH influences the formation of the covalent adduct essential for effective inactivation of MAO.
Topics: Binding Sites; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Inhibitory Concentration 50; Kinetics; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oxidation-Reduction; Protein Binding; Structure-Activity Relationship; Substrate Specificity; Time Factors
PubMed: 33322203
DOI: 10.3390/molecules25245908 -
International Journal of Biological... Nov 2023Monoamine oxidase is a flavin enzyme that catalyzes the oxidation of monoamine neurotransmitters in the brain. Various toxic by-products, aldehydes and hydrogen peroxide... (Review)
Review
Monoamine oxidase is a flavin enzyme that catalyzes the oxidation of monoamine neurotransmitters in the brain. Various toxic by-products, aldehydes and hydrogen peroxide produced during the catalytic process, can cause oxidative stress and neuronal cell death. Overexpression of MAO-B and insufficient dopamine concentration are recognized as pathological factors in neurodegenerative diseases (NDs) including Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, the inhibition of MAO-B is an attractive target for the treatment of NDs. Despite significant efforts, few selective and reversible MAO-B inhibitors have been clinically approved. Natural products have emerged as valuable sources of lead compounds in drug discovery. Compounds such as chromone, coumarin, chalcone, caffeine, and aurone, present in natural structures, are considered as privileged scaffolds in the synthesis of MAO-B inhibitors. In this review, we summarized the structure-activity relationship (SAR) of MAO-B inhibitors based on the naturally privileged scaffolds over the past 20 years. Additionally, we proposed a balanced discussion on the advantages and limitations of natural scaffold-based MAO-B inhibitors with providing a future perspective in drug development.
Topics: Monoamine Oxidase Inhibitors; Monoamine Oxidase; Humans; Structure-Activity Relationship; Biological Products; Animals
PubMed: 37549764
DOI: 10.1016/j.ijbiomac.2023.126158 -
European Journal of Pharmacology Sep 2021Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone...
Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone (GD) effect in vitro to inhibit the A and B isoforms of human monoamine oxidase (hMAO) enzyme and their citotoxicity in human hepatoma cell line (HepG2). Also, binding studies to A, A A and A adenosine receptors were performed. A docking study of gamma-decanolactone has been carried out with the molecular targets of MAO-A and MAO-B isoforms. The physicochemical properties and ability to cross physiological barriers, as the blood brain barrier (BBB), was elucidated by computational studies. The in vivo assays, the rota-rod test, body temperature assessment and open field test were performed in reserpinized mice (1.5 mg/kg, i.p.; 18:00 before) to evaluate the effect of gamma-decanolactone (300 mg/kg), alone or associated with Levodopa plus Benserazide (LD + BZ, 100:25 mg/kg, i.p.). Gamma-decanolactone inhibited preferentially the MAO-B in a reversible manner, with an inhibitory concentration of 50% (IC) 55.95 ± 9.06 μM. It was shown to be a safe drug since only at the highest concentration decreased the viability of HepG2 cells. It also does not bind to adenosine receptors investigated in this study. The molecular docking study show that the gamma-decanolactone ligand adopts a relatively compact conformation in the active site of hMAO-B, while we note an extended conformation of gamma-decanolactone ligand in the hMAO-A isoform. The physicochemical properties obtained, and the theoretical models utilized for the evaluation of ability to cross the BBB, predict a good gamma-decanolactone bioavailability and access to the central nervous system (CNS). In the in vivo studies, gamma-decanolactone partially reversed the ataxia of the reserpinized mice at 01:00 h and 01:30 h post-administration. Concomitant treatment of gamma-decanolactone with LD + BZ, at 01:30 h showed a potentiation of the reversibility of ataxia and facilitated the reversal of hypothermia caused by reserpine for all measured times (P <0.01 vs vehicle), except at 24:00 h, but not reversed the hypokinesia in the open field test. In summary, the results herein obtained and in conjunction with previous studies, suggest that gamma-decanolactone could be a drug with potential utility as antiparkinsonian drug.
Topics: Animals; Antiparkinson Agents; Blood-Brain Barrier; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Assays; Hep G2 Cells; Humans; Lactones; Male; Mice; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Parkinson Disease, Secondary; Permeability; Receptors, Purinergic P1; Recombinant Proteins; Reserpine; Structure-Activity Relationship
PubMed: 34174267
DOI: 10.1016/j.ejphar.2021.174276 -
Bioorganic & Medicinal Chemistry Letters Jul 2022Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the...
Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC = 0.721 µM) compared to MAO-B (IC = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression.
Topics: Humans; Indans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Parkinson Disease; Propylamines; Selegiline; Tetrahydronaphthalenes; Tyramine
PubMed: 35447344
DOI: 10.1016/j.bmcl.2022.128746 -
Future Medicinal Chemistry Nov 2022Design of 5-methoxy benzofuran hybrids with 2-carbohydrazide and 2-(1,3,4-oxadiazol-2-yl) as potential inhibitors of monoamine oxidase (MAO)-B targeting Parkinson...
Design of 5-methoxy benzofuran hybrids with 2-carbohydrazide and 2-(1,3,4-oxadiazol-2-yl) as potential inhibitors of monoamine oxidase (MAO)-B targeting Parkinson disease. 12 compounds were synthesized and analyzed via high-resolution mass spectrometry, H nuclear magnetic resonance and C nuclear magnetic resonance techniques. fluorometric assay was used to investigate the activity of the synthesized compounds on both MAO-A and MAO-B isozymes. Three compounds - , and - displayed half maximal inhibitory concentration values of 0.051 ± 0.002, 0.038 ± 0.001 and 0.077 ± 0.003 μM in the inhibition of MAO-A and 0.048 ± 0.002, 0.040 ± 0.001 and 0.072 ± 0.002 μM for MAO-B, respectively. A molecular dynamics simulation study showed that compound has poor stability as a complex with MAO-A. Compound may be a potential candidate for the treatment of Parkinson disease.
Topics: Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Molecular Docking Simulation; Mass Spectrometry; Structure-Activity Relationship; Molecular Structure
PubMed: 36317547
DOI: 10.4155/fmc-2022-0167 -
European Journal of Medicinal Chemistry Aug 2023Monoamine oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and other cancers. In this...
Design, synthesis, and biological activity of dual monoamine oxidase A and heat shock protein 90 inhibitors, N-Methylpropargylamine-conjugated 4-isopropylresorcinol for glioblastoma.
Monoamine oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and other cancers. In this study, a series of MAO A/HSP90 dual inhibitors were designed and synthesized in the hope to develop more effective treatment of GBM. Compounds 4-b and 4-c are conjugates of isopropylresorcinol (pharmacophore of HSP90 inhibitor) with the phenyl group of clorgyline (MAO A inhibitor) by a tertiary amide bond substituted with methyl (4-b) or ethyl (4-c) group, respectively. They inhibited MAO A activity, HSP90 binding, and the growth of both TMZ-sensitive and -resistant GBM cells. Western blots showed that they increased HSP70 expression indicating reduced function of HSP90, reduced HER2 and phospho-Akt expression similar to MAO A or HSP90 inhibitor itself. Both compounds decreased IFN-γ induced PD-L1 expression in GL26 cells, suggesting they can act as immune checkpoint inhibitor. Further, they reduced tumor growth in GL26 mouse model. NCI-60 analysis showed they also inhibited the growth of colon cancer, leukemia, non-small cell lung and other cancers. Taken together, this study demonstrates MAO A/HSP90 dual inhibitors 4-b and 4-c reduced the growth of GBM and other cancers, and they have potential to inhibit tumor immune escape.
Topics: Mice; Animals; Monoamine Oxidase; Glioblastoma; Monoamine Oxidase Inhibitors; Clorgyline; Antineoplastic Agents; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins
PubMed: 37172473
DOI: 10.1016/j.ejmech.2023.115459