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International Journal of Molecular... May 2023To facilitate the identification of novel MAO-B inhibitors, we elaborated a consolidated computational approach, including a pharmacophoric atom-based 3D quantitative...
To facilitate the identification of novel MAO-B inhibitors, we elaborated a consolidated computational approach, including a pharmacophoric atom-based 3D quantitative structure-activity relationship (QSAR) model, activity cliffs, fingerprint, and molecular docking analysis on a dataset of 126 molecules. An AAHR.2 hypothesis with two hydrogen bond acceptors (A), one hydrophobic (H), and one aromatic ring (R) supplied a statistically significant 3D QSAR model reflected by the parameters: R = 0.900 (training set); Q = 0.774 and Pearson's R = 0.884 (test set), stability s = 0.736. Hydrophobic and electron-withdrawing fields portrayed the relationships between structural characteristics and inhibitory activity. The quinolin-2-one scaffold has a key role in selectivity towards MAO-B with an AUC of 0.962, as retrieved by ECFP4 analysis. Two activity cliffs showing meaningful potency variation in the MAO-B chemical space were observed. The docking study revealed interactions with crucial residues TYR:435, TYR:326, CYS:172, and GLN:206 responsible for MAO-B activity. Molecular docking is in consensus with and complementary to pharmacophoric 3D QSAR, ECFP4, and MM-GBSA analysis. The computational scenario provided here will assist chemists in quickly designing and predicting new potent and selective candidates as MAO-B inhibitors for MAO-B-driven diseases. This approach can also be used to identify MAO-B inhibitors from other libraries or screen top molecules for other targets involved in suitable diseases.
Topics: Monoamine Oxidase Inhibitors; Molecular Docking Simulation; Monoamine Oxidase; Quantitative Structure-Activity Relationship; Pharmacophore; Structure-Activity Relationship
PubMed: 37298535
DOI: 10.3390/ijms24119583 -
Journal of Medicinal Chemistry Nov 2023The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple...
The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HTR antagonism and interaction with 5-HTR were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HTR antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HTR/5-HTR/MAO-B in AD.
Topics: Rats; Animals; Serotonin; Cryoelectron Microscopy; Receptors, Serotonin; Serotonin Antagonists; Alzheimer Disease; Monoamine Oxidase; Cognition; Monoamine Oxidase Inhibitors
PubMed: 37797083
DOI: 10.1021/acs.jmedchem.3c01482 -
Molecules (Basel, Switzerland) Dec 2019A series of 4-aminomethyl-7-benzyloxy-2-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE...
A series of 4-aminomethyl-7-benzyloxy-2-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (, , , , ) showing nanomolar and selective MAO B inhibition along with IC against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.
Topics: Cholinesterase Inhibitors; Coumarins; Drug Evaluation, Preclinical; Enzyme Activation; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Monoamine Oxidase Inhibitors; Structure-Activity Relationship; para-Aminobenzoates
PubMed: 31835376
DOI: 10.3390/molecules24244507 -
Journal of Enzyme Inhibition and... Dec 20223-arylcoumarins with different pharmacological properties widely exist in a variety of natural plants. The extensive research on 3-arylcoumarins was attributed to its... (Review)
Review
3-arylcoumarins with different pharmacological properties widely exist in a variety of natural plants. The extensive research on 3-arylcoumarins was attributed to its therapeutic and relatively easy isolation. Therefore, 3-arylcoumarins can be recognised as useful structures for the design of novel compounds with potential pharmacological interest, particularly in the fields of anti-inflammatory, anti-cancer, antioxidant, Monoamine oxidase (MAO) enzyme inhibition, etc. The current review highlights the biological activities, design, and chemical synthetic methods of 3-arylcoumarins derivatives as well as their important natural product sources.
Topics: Antioxidants; Coumarins; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 35438580
DOI: 10.1080/14756366.2022.2058499 -
Molecules (Basel, Switzerland) Mar 2023A quinoline-malononitrile (QM)-based aggregation-induced emission probe was developed to detect MAOs in cells through an enzymatic reaction followed by β-elimination....
A quinoline-malononitrile (QM)-based aggregation-induced emission probe was developed to detect MAOs in cells through an enzymatic reaction followed by β-elimination. After being incubated at 37 °C, responded to the MAO enzymes with great specificity and within just 5 min. This 5 min responsive mechanism was fast, with the limit of detection (LOD) at 5.49 and 4.76 µg mL for MAO-A and MAO-B, respectively. Moreover, displayed high enzyme specificity even in the presence of high concentrations of biological interferences, such as oxidizing and reducing agents, biothiols, amino acids, and glucose. Furthermore, demonstrated biocompatibility as the cells retained more than 70% viability when exposed to at concentrations of up to 20 µM. As a result, was used to detect MAO-A and MAO-B in SH-SY5Y and HepG2 cells, respectively. After 1h incubation with , the cells exhibited enhanced fluorescence by about 20-fold. Moreover, the signal from cells was reduced when MAO inhibitors were applied prior to incubating with . Therefore, our research recommends using a QM probe as a generic method for producing recognition moieties for fluorogenic enzyme probes.
Topics: Humans; Neuroblastoma; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Quinolines
PubMed: 36985627
DOI: 10.3390/molecules28062655 -
The FEBS Journal Aug 2015Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based...
Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition, most compounds gave high IC50 values with MAO A, but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme, the inhibition was irreversible for both MAO A and MAO B, and the activity was not restored by dilution. Spectral changes during inactivation of MAO A included bleaching at 456 nm and an increased absorbance at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5 nm for MAO B and 170 nm for MAO A after 30 min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1.
Topics: Antidepressive Agents; Catalytic Domain; Cyclopropanes; Histone Demethylases; Humans; In Vitro Techniques; Kinetics; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Stereoisomerism; Structure-Activity Relationship; Tranylcypromine
PubMed: 25755053
DOI: 10.1111/febs.13260 -
Journal of Psychiatry & Neuroscience :... Mar 1997The importance of continuation and maintenance antidepressant therapy has been increasingly recognized, but usually focuses on tricyclic and selective serotonin reuptake... (Comparative Study)
Comparative Study Review
The importance of continuation and maintenance antidepressant therapy has been increasingly recognized, but usually focuses on tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants. This review examines the evidence in support of classical monoamine oxidase inhibitor (MAOI) agents and the selective reversible monoamine oxidase type A inhibitor moclobemide in continuation and maintenance therapy. Phenelzine and tranylcypromine have demonstrated long-term efficacy but often cause intolerable side effects. Moclobemide is a well-tolerated alternative antidepressant, but there is a need for prospective controlled trials to evaluate its long-term efficacy.
Topics: Antidepressive Agents; Depressive Disorder; Dose-Response Relationship, Drug; Humans; Long-Term Care; Monoamine Oxidase Inhibitors; Phenelzine; Tranylcypromine; Treatment Outcome
PubMed: 9074307
DOI: No ID Found -
The Cochrane Database of Systematic... Jul 2005It has been postulated that monoamine oxidase B (MAO-B) inhibitors alter disease progression in Parkinson's disease (PD). Clinical trials have produced conflicting... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
It has been postulated that monoamine oxidase B (MAO-B) inhibitors alter disease progression in Parkinson's disease (PD). Clinical trials have produced conflicting results.
OBJECTIVES
To assess the evidence from randomized controlled trials for the effectiveness and safety of long-term use of MAO-B inhibitors in early PD.
SEARCH STRATEGY
We searched the following electronic databases: Cochrane Central Register of Controlled trials (CENTRAL) (The Cochrane Library Issue 2, 2004), MEDLINE (last searched 18th August 2004) and EMBASE (last searched 18th August 2004). We also handsearched neurology and movement disorders conference proceedings, checked reference lists of relevant studies and contacted other researchers.
SELECTION CRITERIA
We sought to include all unconfounded randomized controlled trials that compared a MAO-B inhibitor with control, in the presence or absence of levodopa or dopamine agonists, in patients with early PD and where treatment and follow up lasted at least one year.
DATA COLLECTION AND ANALYSIS
Two reviewers independently selected trials for inclusion, assessed the methodological quality, and extracted the data. A small amount of additional data was provided by the original authors. Random-effects models were used to analyse results, where appropriate.
MAIN RESULTS
Ten trials were included (a total of 2422 patients), nine using selegiline, one using lazabemide. The methodological quality was reasonable although concealment of allocation was definitely adequate in only four trials. The mean follow up was for 5.8 years. MAO-B inhibitors were not associated with a significant increase in deaths (odds ratio (OR) 1.15; 95% confidence interval (CI) 0.92 to 1.44). They provided small benefits over control in impairment (weighted mean difference (WMD) for change in motor UPDRS score was 3.81 points less with MAO-B inhibitors; 95% CI 2.27 to 5.36) and disability (WMD for change in UPDRS ADL score was 1.50 less; 95% CI 0.48 to 2.53) at one year which, although statistically significant, were not clinically significant. There was a marked levodopa-sparing effect with MAO-B inhibitors which was associated with a significant reduction in motor fluctuations (OR 0.75; 95% CI 0.59 to 0.94) but not dyskinesia (OR 0.97; 95% CI 0.76 to 1.25). The reduction in motor fluctuations was, however, not robust in sensitivity analyses. Although adverse events were generally mild and infrequent, withdrawals due to side-effects were higher (OR 2.36; 95% CI 1.32 to 4.20) with MAO-B inhibitors.
AUTHORS' CONCLUSIONS
MAO-B inhibitors do not appear to delay disease progression but may have a beneficial effect on motor fluctuations. There was no statistically significant effect on deaths although the confidence interval does not exclude a small increase with MAO-B inhibitors. At present we do not feel these drugs can be recommended for routine use in the treatment of early Parkinson's disease but further randomized controlled trials should be carried out to clarify, in particular, their effect on deaths and motor complications.
Topics: Antiparkinson Agents; Dopamine Agonists; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Picolinic Acids; Randomized Controlled Trials as Topic; Selegiline
PubMed: 16034956
DOI: 10.1002/14651858.CD004898.pub2 -
Molecules (Basel, Switzerland) Jul 2022Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that... (Review)
Review
Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that patients with atypical depression preferentially respond to natural product MAOIs. This review presents a comprehensive survey of the natural products, predominantly from plant sources, as potential new MAOI drug leads. The psychoactive properties of several traditionally used plants and herbal formulations were attributed to their MAOI constituents. MAO inhibitory constituents may also be responsible for neuroprotective effects of natural products. Different classes of MAOIs were identified from the natural product sources with non-selective as well as selective inhibition of MAO-A and -B. Selective reversible natural product MAOIs may be safer alternatives to the conventional MAOI drugs. Characterization of MAO inhibitory constituents of natural products traditionally used as psychoactive preparations or for treatment of neurological disorders may help in understanding the mechanism of action, optimization of these preparations for desired bioactive properties, and improvement of the therapeutic potential. Potential therapeutic application of natural product MAOIs for treatment of neuroblastoma is also discussed.
Topics: Biological Products; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nervous System Diseases; Neuroblastoma; Neuroprotection
PubMed: 35807542
DOI: 10.3390/molecules27134297 -
Arquivos de Neuro-psiquiatria Sep 2001Social anxiety disorder (SAD) is a marked and persistent fear of doing almost everything in front of people due to concerns about being judge by others. An up-to-date... (Review)
Review
Social anxiety disorder (SAD) is a marked and persistent fear of doing almost everything in front of people due to concerns about being judge by others. An up-to-date review is needed in order to reach a practical judgement of all psychopharmacological data. Case reports, open and double-blind trials with SAD were described and commented upon from a clinical point of view. The MEDLINE system was searched from 1975 to 2001. The references from the selected papers were also used as a source. MAOIs (fenelzine, tranylcypromine), reversible monoamino oxidase-A inhibitors (moclobemide, brofaromine), SSRIs (paroxetine, sertraline, fluoxetine, fluvoxamine) and some other antidepressants (venlafaxine, nefazodone) have proven effective in several studies with various methodologies. The MAOIs have more serious adverse effects and the SSRIs have the best tolerance. SSRIs are efficacious and the first choice of treatment.
Topics: Antidepressive Agents; Humans; Monoamine Oxidase Inhibitors; Phobic Disorders; Selective Serotonin Reuptake Inhibitors
PubMed: 11588653
DOI: 10.1590/s0004-282x2001000400032