scholarly journals Estrogen-Related Receptors-Stimulated Monoamine Oxidase B Promoter Activity Is Down-Regulated by Estrogen Receptors

2006 ◽  
Vol 20 (7) ◽  
pp. 1547-1561 ◽  
Author(s):  
Zhiping Zhang ◽  
Kevin Chen ◽  
Jean C. Shih ◽  
Christina T. Teng
Keyword(s):  
Monoamine Oxidase ◽  
Promoter Activity ◽  
Target Genes ◽  
Neuroprotective Effect ◽  
Estrogen Receptor Α ◽  
Degradation Pathway ◽  
Gene Activity ◽  
Monoamine Oxidase A ◽  
Independent Manner ◽  
Mao B

Abstract Although there are studies published about the neuroprotective effect of estrogen, little is known about the mechanisms and cellular targets of the hormone. Recent reports demonstrate that estrogen down-regulates the expression of monoamine oxidase A and B (MAO-A and MAO-B) in the hypothalamus of the Macaques monkey, both of which are key isoenzymes in the neurotransmitter degradation pathway. Additionally, estrogen-related receptor α (ERRα) up-regulates MAO-B gene expression in breast cancer cells. ERRα recognizes a variety of estrogen response elements and shares many target genes and coactivators with estrogen receptor α (ERα). In this study, we investigate the interplay of ERs and ERRs in the regulation of MAO-B promoter activity. We demonstrate that ERRα and ERRγ up-regulate MAO-B gene activity, whereas ERα and ERβ decrease stimulation in both a ligand-dependent and -independent manner. Ectopically expressed ERRα and ERRγ stimulate the expression of MAO-B mRNA and protein as well as increase the MAO-B enzymatic activity in ER-negative HeLa cells. The ability of ERRs to stimulate MAO-B promoter activity was reduced in ER-positive MCF-7 and T47D cells. Several AGGTCA motifs of the MAO-B promoter are responsible for up-regulation by ERRs. Interestingly, ERα or ERβ alone have no effect on MAO-B promoter activity but can down-regulate the activation function of ERRs, whereas glucocorticoid receptor does not. By using chromatin immunoprecipitation assay, we demonstrate that ERs compete with ERRs for binding to the MAO-B promoter at selective AGGTCA motifs, thereby changing the chromatin status and cofactor recruitment to a repressed state. These studies provide new insight into the relationship between ERα, ERβ, ERRα, and ERRγ in modulation of MAO-B gene activity.

scholarly journals Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3264
Author(s):  
Aathira Sujathan Nair ◽  
Jong-Min Oh ◽  
Vishal Payyalot Koyiparambath ◽  
Sunil Kumar ◽  
Sachithra Thazhathuveedu Sudevan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Monoamine Oxidase ◽  
Phenyl Ring ◽  
Competitive Inhibitor ◽  
Selectivity Index ◽  
Monoamine Oxidase A ◽  
Mao B ◽  
Ic50 Value ◽  
The Central Nervous System ◽  
Inhibitory Activities

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of –F (in EH7) > –Cl (EH6) > –Br (EH8) > –H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.

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.

The Design and Evaluation of a Novel Monoamine Oxidase B Inhibitor Through in Silico Approach

2019 ◽  
Vol 10 (02) ◽  
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Safaa Muhsen Kareem ◽  
Mohammed Ridha A Alhaideri ◽  
Mohammed Abbas Hasan ◽  
Werner J Geldenhuys
Keyword(s):  
Monoamine Oxidase ◽  
In Silico ◽  
Neuroprotective Effect ◽  
Monoamine Oxidase B ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mao B ◽  
Age Related ◽  
Novel Scaffold

Parkinson’s disease is an age related neurodegenerative disease. Pioglitazone is a Peroxisome proliferator-activated receptor gamma agonist that has been shown to display a neuroprotective effect in parkinsonian models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mice). This effect was partially attributed to the ability of thiazolidinedione (TZD) moiety in Pioglitazone to selectively inhibit monoamine oxidase B (MAO-B) enzyme. In the current study, we screened several thiazolidine containing compounds against MAO-B enzyme both in silico and in vitro. Based on the resulted data and information from previous literatures, we were able to design a novel scaffold for MAO-B inhibitors. This scaffold (compound 5482440) was able to inhibit MAO-B enzyme with IC50 value of 1.447 μM. Structure-based virtual analysis showed that this compound was able to participate in water-bridge formation and obtain an extended conformation within MAO-B active site.

Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer’s Disease

2019 ◽  
Vol 18 (8) ◽  
pp. 643-654 ◽  
Author(s):  
Reeta ◽  
Seung Cheol Baek ◽  
Jae Pil Lee ◽  
T.M. Rangarajan ◽  
Ayushee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoamine Oxidase ◽  
Target Prediction ◽  
Inhibitory Effect ◽  
Monoamine Oxidase A ◽  
Mao B ◽  
Drug Molecules ◽  
Ic50 Value ◽  
Ic50 Values

Background: Chalcones are considered as the selective scaffold for the inhibition of MAO-B. Objective: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer’s Disease (AD). Methods: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed. Results: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively. Conclusion: The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.

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.

scholarly journals Alkaloids of Peganum harmala L. and their Pharmacological Activity

2021 ◽  
Vol 9 (A) ◽  
pp. 766-775
Author(s):  
Aidos Doskaliyev ◽  
Roza Seidakhmetova ◽  
D. S. Tutai ◽  
Kristina Goldaeva ◽  
V.K. Surov ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Dopamine D2 Receptor ◽  
Neuroprotective Effect ◽  
Monoamine Oxidase A ◽  
Antihypoxic Activity ◽  
Toxic Substances ◽  
Peganum Harmala ◽  
Hazard Class ◽  
Reference Drug ◽  
Pharmacologically Active

Peganum harmala L. contains 17 alkaloids of quinazoline and indole structure types. Of these, harmaline, harmine, harmalol and L-peganin (vazicin) are pharmacologically active. It was established that of the alkaloids contained in the seeds, 50-95% is dominated by harmaline, harmine is dominated in the roots (67-74% of the total of extractive substances), and in the aerial part, the main mass is peganin (up to 78% of the total of alkaloids). Beta-carboline alkaloids of Peganum harmala L. inhibit monoamine oxidase, thereby exerting a neuroprotective effect. This article is devoted to the results of studies of the neurotropic action of harmine hydrochloride, when compared with the activity of the reference drug “Amitriptyline”. It was shown that the use of harmine hydrochloride helps to reduce the level of anxiety in animals under conditions of experimental psychoemotional chronic stress with prolonged administration. In the study of acute and chronic toxicity, it was determined that harmine hydrochloride belongs to the category of moderately toxic substances (hazard class II). According to the results of molecular docking, the presence of strong bonds in harmine hydrochloride with the serotonin 5-HT2C receptor, dopamine D2 receptor, as well as monoamine oxidase A and B was revealed, which indicates the implementation of the mechanism of neurotropic action of harmine hydrochloride at the level of synaptic neurotransmission of monoamines (dopamine, serotonin and others). It was also established that harmine hydrochloride eliminates haloperidol-induced catalepsy in rats, reduces oligokinesia and rigidity in the Parkinson’s test, has antihypoxic activity in the hypobaric hypoxia test, and exhibits pronounced antidepressant activity in the Porsolt’s test. In the course of the study of pharmacokinetics and bioavailability, it was revealed that with the administration of harmine hydrochloride, the quantitative content is quickly achieved and the concentration of the active substance in the blood significantly increases. The relative bioavailability of harmine hydrochloride is 112.7%.

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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