scholarly journals Interactions of Desmethoxyyangonin, a Secondary Metabolite fromRenealmia alpinia, with Human Monoamine Oxidase-A and Oxidase-B

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Narayan D. Chaurasiya ◽  
Francisco León ◽  
Yuanqing Ding ◽  
Isabel Gómez-Betancur ◽  
Dora Benjumea ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Equilibrium Dialysis ◽  
Monoamine Oxidase A ◽  
Tropical Rainforests ◽  
Reversible Binding ◽  
Mao B ◽  
Potent Inhibition ◽  
Mao A ◽  
Preferential Binding ◽  
Phytochemical Studies

Renealmia alpinia(Zingiberaceae), a medicinal plant of tropical rainforests, is used to treat snakebites and other injuries and also as a febrifuge, analgesic, antiemetic, antiulcer, and anticonvulsant. The dichloromethane extract ofR. alpinialeaves showed potent inhibition of human monoamine oxidases- (MAOs-) A and B. Phytochemical studies yielded six known compounds, including pinostrobin1, 4′-methyl ether sakuranetin2, sakuranetin3, pinostrobin chalcone4, yashabushidiol A5, and desmethoxyyangonin6. Compound6displayed about 30-fold higher affinity for MAO-B than MAO-A, with Ki values of 31 and 922 nM, respectively. Kinetic analysis of inhibition and equilibrium-dialysis dissociation assay of the enzyme-inhibitor complex showed reversible binding of desmethoxyyangonin6with MAO-A and MAO-B. The binding interactions of compound6in the active site of the MAO-A and MAO-B isoenzymes, investigated through molecular modeling algorithms, confirmed preferential binding of desmethoxyyangonin6with MAO-B compared to MAO-A. Selective reversible inhibitors of MAO-B, like desmethoxyyangonin6,may have important therapeutic significance for the treatment of neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease.

scholarly journals Microbial Metabolite Urolithin B Inhibits Recombinant Human Monoamine Oxidase A Enzyme

Metabolites ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 258
Author(s):  
Rajbir Singh ◽  
Sandeep Chandrashekharappa ◽  
Praveen Kumar Vemula ◽  
Bodduluri Haribabu ◽  
Venkatakrishna Rao Jala
Keyword(s):  
Monoamine Oxidase ◽  
Enzyme Inhibitor ◽  
Monoamine Oxidase A ◽  
Mao B ◽  
Functional Activities ◽  
Mao A ◽  
Mao Activity ◽  
Anti Oxidant ◽  
Urolithin B

Urolithins are gut microbial metabolites derived from ellagitannins (ET) and ellagic acid (EA), and shown to exhibit anticancer, anti-inflammatory, anti-microbial, anti-glycative and anti-oxidant activities. Similarly, the parent molecules, ET and EA are reported for their neuroprotection and antidepressant activities. Due to the poor bioavailability of ET and EA, the in vivo functional activities cannot be attributed exclusively to these compounds. Elevated monoamine oxidase (MAO) activities are responsible for the inactivation of monoamine neurotransmitters in neurological disorders, such as depression and Parkinson’s disease. In this study, we examined the inhibitory effects of urolithins (A, B and C) and EA on MAO activity using recombinant human MAO-A and MAO-B enzymes. Urolithin B was found to be a better MAO-A enzyme inhibitor among the tested urolithins and EA with an IC50 value of 0.88 µM, and displaying a mixed mode of inhibition. However, all tested compounds exhibited higher IC50 (>100 µM) for MAO-B enzyme.

scholarly journals Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana)

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 810 ◽  
Author(s):  
Narayan Chaurasiya ◽  
Jianping Zhao ◽  
Pankaj Pandey ◽  
Robert Doerksen ◽  
Ilias Muhammad ◽  
...  
Keyword(s):  
Methyl Ether ◽  
Enzyme Inhibitor ◽  
Equilibrium Dialysis ◽  
Selective Inhibition ◽  
Standard Drug ◽  
Mao B ◽  
Turnera Diffusa ◽  
Mechanism Of Inhibition ◽  
Mao A

The investigation of the constituents that were isolated from Turnera diffusa (damiana) for their inhibitory activities against recombinant human monoamine oxidases (MAO-A and MAO-B) in vitro identified acacetin 7-methyl ether as a potent selective inhibitor of MAO-B (IC50 = 198 nM). Acacetin 7-methyl ether (also known as 5-hydroxy-4′, 7-dimethoxyflavone) is a naturally occurring flavone that is present in many plants and vegetables. Acacetin 7-methyl ether was four-fold less potent as an inhibitor of MAO-B when compared to acacetin (IC50 = 50 nM). However, acacetin 7-methyl ether was >500-fold selective against MAO-B over MAO-A as compared to only two-fold selectivity shown by acacetin. Even though the IC50 for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., SelegilineTM or ZelaparTM, a selective MAO-B inhibitor), acacetin 7-methyl ether’s selectivity for MAO-B over MAO-A inhibition was greater than that of deprenyl (>500- vs. 450-fold). The binding of acacetin 7-methyl ether to MAO-B was reversible and time-independent, as revealed by enzyme-inhibitor complex equilibrium dialysis assays. The investigation on the enzyme inhibition-kinetics analysis with varying concentrations of acacetin 7-methyl ether and the substrate (kynuramine) suggested a competitive mechanism of inhibition of MAO-B by acacetin 7-methyl ether with Ki value of 45 nM. The docking scores and binding-free energies of acacetin 7-methyl ether to the X-ray crystal structures of MAO-A and MAO-B confirmed the selectivity of binding of this molecule to MAO-B over MAO-A. In addition, molecular dynamics results also revealed that acacetin 7-methyl ether formed a stable and strong complex with MAO-B. The selective inhibition of MAO-B suggests further investigations on acacetin 7-methyl as a potential new drug lead for the treatment of neurodegenerative disorders, including Parkinson’s disease.

scholarly journals Parameters for Irreversible Inactivation of Monoamine Oxidase

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5908
Author(s):  
Rona R. Ramsay ◽  
Livia Basile ◽  
Antonin Maniquet ◽  
Stefanie Hagenow ◽  
Matteo Pappalardo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Hydrophobic Interactions ◽  
Irreversible Inhibitor ◽  
Reversible Binding ◽  
Mao B ◽  
Irreversible Inhibitors ◽  
Aromatic Cage ◽  
Covalent Adduct ◽  
Mao A ◽  
New Compounds

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 Ki 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.

Are Coumarin Derivatives The New Keys in Depression Treatment? In silico Key-lock Fitting Analysis of Coumarin Derivatives with Monoamine Oxidase-A

2020 ◽  
Vol 7 ◽  
Author(s):  
Dilara Karaman ◽  
Kemal YELEKCI ◽  
Serkan ALTUNTAS
Keyword(s):  
Monoamine Oxidase ◽  
Protein Interactions ◽  
In Silico ◽  
Monoamine Oxidase A ◽  
Coumarin Derivatives ◽  
Discovery Studio ◽  
Mao B ◽  
Drug Candidates ◽  
Mao A ◽  
Molecular Modeling Studies

The research of ligand-protein interactions with in silico molecular modeling studies on the atomic level gives an opportunity to be understood the pharmacokinetic metabolism of anti-depressant drug candidates. Monoamine oxidase (MAO) enzymes are important targets for the treatment of depressive disorder. MAOs have two isoforms as MAO-A and MAO-B being responsible for catalyzing of neurological amines. In this study a new series of coumarin derivatives were designed for selective and reversible inhibition of MAO-A enzyme. 3rd, 5th and 7th positions were selected to be placed of five different side groups. Docking procedures of each ligand in M series of these novel 125 compounds were executed with 10 runs by using AutoDock4.2 software. Docking results were analyzed via Discovery Studio 3.1 (Biovia Inc.). The most promising compounds were M118 and M123 according to selectivity index, SI (MAO-B/MAO-A)=180 fold and 209 fold and Ki values 7.25 nM and 12.01 nM, respectively. Overall, the current study provided significant knowledge for the development of new anti-depressant drugs.

scholarly journals How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5962 ◽  
Author(s):  
Anne Wurzlbauer ◽  
Katharina Rüben ◽  
Ece Gürdal ◽  
Apirat Chaikuad ◽  
Stefan Knapp ◽  
...  
Keyword(s):  
De Novo ◽  
Binding Mode ◽  
Crystal Structure Analysis ◽  
Monoamine Oxidase A ◽  
Direct Modification ◽  
Structure Activity ◽  
Potent Inhibition ◽  
Mao A ◽  
Systematic Structure ◽  
Polar Substituents

The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure–activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors.

scholarly journals Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5358
Author(s):  
Narayan D. Chaurasiya ◽  
Jacob Midiwo ◽  
Pankaj Pandey ◽  
Regina N. Bwire ◽  
Robert J. Doerksen ◽  
...  
Keyword(s):  
Natural Products ◽  
Enzyme Inhibition ◽  
Selective Inhibition ◽  
Monoamine Oxidase A ◽  
Inhibition Kinetics ◽  
Free Energies ◽  
Mao B ◽  
Mao A ◽  
Enzyme Inhibition Kinetics ◽  
Binding Free Energies

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1–3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4–6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC50 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.

scholarly journals Isolation and Biological Evaluation of Prenylated Flavonoids from Maclura pomifera

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yerkebulan Orazbekov ◽  
Mohamed A. Ibrahim ◽  
Serjan Mombekov ◽  
Radhakrishnan Srivedavyasasri ◽  
Ubaidilla Datkhayev ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Opioid Receptors ◽  
Cannabinoid Receptors ◽  
Biological Evaluation ◽  
Monoamine Oxidase A ◽  
Moderate Activity ◽  
Significant Activity ◽  
Mao B ◽  
Maclura Pomifera ◽  
Mao A

Phytochemical analysis of the ethanolic extract of Maclura pomifera fruits yielded four new compounds (I–IV) along with eleven known compounds (V–XV). The crude extract exhibited significant activity towards cannabinoid receptors (CB1: 103.4% displacement; CB2: 68.8% displacement) and possibly allosteric interaction with δ and μ opioid receptors (−49.7 and −53.8% displacement, resp.). Compound I was found to be possibly allosteric for κ and μ opioid receptors (−88.4 and −27.2% displacement, resp.) and showed moderate activity (60.5% displacement) towards CB1 receptor. Compound II exhibited moderate activity towards cannabinoid receptors CB1 and CB2 (47.9 and 42.3% displacement, resp.). The known compounds (V–VIII) exhibited prominent activity towards cannabinoid receptors: pomiferin (V) (IC50 of 2.110 and 1.318 μM for CB1 and CB2, resp.), auriculasin (VI) (IC50 of 8.923 μM for CB1), warangalone (VII) (IC50 of 1.670 and 4.438 μM for CB1 and CB2, resp.), and osajin (VIII) (IC50 of 3.859 and 7.646 μM for CB1 and CB2, resp.). The isolated compounds were also tested for inhibition of human monoamine oxidase-A and monoamine oxidase-B enzymes activities, where all the tested compounds showed fewer inhibitory effects on MAO-A compared to MAO-B activities: auriculasin (VI) (IC50 of 1.91 and 45.98 μM for MAO-B and MAO-A, resp.).

scholarly journals Histochemical investigation of criteria for the distinction between monoamine oxidase A and B in various species.

1984 ◽  
Vol 32 (6) ◽  
pp. 667-673 ◽  
Author(s):  
E Uchida ◽  
G B Koelle
Keyword(s):  
Dorsal Root Ganglion ◽  
Monoamine Oxidase ◽  
Dorsal Root ◽  
Monoamine Oxidase A ◽  
Rat Tissues ◽  
Histochemical Investigation ◽  
Mao B ◽  
Total Inhibition ◽  
Mao A ◽  
Cervical Ganglion

The superior cervical ganglion (SCG), pineal body (PB), and liver (L) of the rat, rabbit and cat were stained for monoamine oxidase (MAO) A and B by the tetranitro blue tetrazolium (TNBT) and coupled peroxidase ( PerOx ) methods, using 5-hydroxytryptamine (5HT), tryptamine ( Tryp ), tyramine (Tyr), and benzylamine (Bz) as substrates, and clorgyline (Cl) and deprenyl (Dep), both at 10(-7) M, as selective inhibitors. The nodose ganglion (NG) and dorsal root ganglion (DRG) of the rabbit and cat were also studied. The results with rat tissues were consistent with published quantitative findings (SCG, MAO-A much greater than B; PB, MAO-A less than or equal to B; L, MAO-A = B). In the rabbit, the findings with the SCG were similar; the MAO activities of the PB were relatively resistant to both inhibitors; the MAO of the liver required 10(-4) M concentrations of both inhibitors to produce near total inhibition, suggesting that the liver contains an MAO distinct from MAO A and B. All cat tissues examined appeared to contain almost exclusively MAO-B. In this species 5HT, which is generally considered a selective substrate for MAO-A, was oxidized by MAO-B. The findings indicate that criteria for MAO-A, -B, and other subgroups must be defined for each species and tissue.

Developing a Multi-target Model to Predict the Activity of Monoamine Oxidase A and B Drugs

2020 ◽  
Vol 20 (18) ◽  
pp. 1593-1600 ◽  
Author(s):  
Riccardo Concu ◽  
Michael González-Durruthy ◽  
Maria Natália D.S. Cordeiro
Keyword(s):  
Side Effects ◽  
Monoamine Oxidase ◽  
Statistical Tests ◽  
Qsar Model ◽  
Monoamine Oxidase A ◽  
Mao Inhibitors ◽  
Computational Approaches ◽  
Linear Discriminant ◽  
Mao B ◽  
Mao A

Introduction: Monoamine oxidase inhibitors (MAOIs) are compounds largely used in the treatment of Parkinson’s disease (PD), Alzheimer’s disease and other neuropsychiatric disorders since they are closely related to the MAO enzymes activity. The two isoforms of the MAO enzymes, MAO-A and MAO-B, are responsible for the degradation of monoamine neurotransmitters and due to this, relevant efforts have been devoted to finding new compounds with more selectivity and less side effects. One of the most used approaches is based on the use of computational approaches since they are time and money-saving and may allow us to find a more relevant structure-activity relationship. Objectives: In this manuscript, we will review the most relevant computational approaches aimed at the prediction and development of new MAO inhibitors. Subsequently, we will also introduce a new multitask model aimed at predicting MAO-A and MAO-B inhibitors. Methods: The QSAR multi-task model herein developed was based on the use of the linear discriminant analysis. This model was developed gathering 5,759 compounds from the public dataset Chembl. The molecular descriptors used was calculated using the Dragon software. Classical statistical tests were performed to check the validity and robustness of the model. Results: The herein proposed model is able to correctly classify all the 5,759 compounds. All the statistical performed tests indicated that this model is robust and reproducible. Conclusion: MAOIs are compounds of large interest since they are largely used in the treatment of very serious illness. These inhibitors may lose efficacy and produce severe side effects. Due to this, the development of selective MAO-A or MAO-B inhibitors is crucial for the treatment of these diseases and their effects. The herein proposed multi-target QSAR model may be a relevant tool in the development of new and more selective MAO inhibitors.

Thyroid iodide transport is reduced by administration of monoamine oxidase A inhibitors to rats

1994 ◽  
Vol 143 (2) ◽  
pp. 303-308 ◽  
Author(s):  
A M Cabanillas ◽  
A M Masini-Repiso ◽  
M E Costamagna ◽  
C Pellizas ◽  
A H Coleoni
Keyword(s):  
Monoamine Oxidase ◽  
Transport Mechanism ◽  
Monoamine Oxidase A ◽  
Mao Inhibitors ◽  
Iodide Uptake ◽  
Mao B ◽  
Iodide Transport ◽  
Mao A ◽  
Mao Activity

Abstract The present work was addressed to study a possible relationship between monoamine oxidase (MAO) and the thyroid iodide transport mechanism. Normal rats treated with clorgyline (a selective MAO-A inhibitor) or tranylcypromine (a non-selective MAO inhibitor) showed a significantly diminished thyroid MAO activity, while deprenyl and pargyline (MAO-B inhibitors) did not modify the thyroidal enzyme activity with respect to the control group. Under these conditions, in vivo iodide transport was reduced both by clorgyline and tranylcypromine administration whereas it remained unchanged after treatment with MAO-B inhibitors. The effect of MAO inhibitors on thyroid MAO activity and in vivo iodide transport was also evaluated in rats treated with exogenous thyrotrophin (TSH) after endogenous TSH secretion blockade produced by T4 administration. In this condition, thyroid MAO activity was significantly lowered by clorgyline and was not modified by deprenyl. In contrast to the results observed in normal rats, in vivo iodide transport in TSH-treated rats remained unaltered after treatment either with clorgyline or deprenyl. MAO activity evaluated in bovine thyroid follicles in primary culture was highly sensitive to low concentrations of clorgyline (<10 nmol/l) and relatively insensitive to deprenyl, a finding that indicates a predominance of the MAO-A isoform in the follicular cells in culture. When clorgyline (0·1 and 1 μmol/l) or deprenyl (1 μmol/l) were added to the culture medium, no modifications in the active transport of iodide were observed. These results indicate the absence of a direct linkage between thyroid MAO activity and the active iodide transport. MAO inhibitors (particularly MAO-A inhibitors) do not appear to be responsible for an in vivo diminished thyroid iodide uptake through a direct action on the iodide transport mechanism. An indirect effect of MAO-A inhibitors on thyroid iodide transport mediated by the accumulation of monoamines in neuroendocrine areas involved in TSH regulation is suggested. Journal of Endocrinology (1994) 143, 303–308

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