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Journal of Molecular Graphics &... Jul 2023An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel... (Review)
Review
An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer's disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives - Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.
Topics: Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Alzheimer Disease; Molecular Docking Simulation; Diflunisal; Drug Repositioning; Reproducibility of Results; Cholinesterase Inhibitors; Acetylcholinesterase
PubMed: 37087882
DOI: 10.1016/j.jmgm.2023.108471 -
Antidepressant effects of coumarins and their derivatives: A critical analysis of research advances.European Journal of Pharmacology Oct 2023Coumarins and their derivatives are non-flavonoids polyphenols with diverse pharmacological activities including anti-depressant effects. This study systematically... (Review)
Review
Coumarins and their derivatives are non-flavonoids polyphenols with diverse pharmacological activities including anti-depressant effects. This study systematically examines the antidepressant effects of coumarins and their derivatives in relation to time series of research progress in the pharmacological pathways, association with other diseases, toxicity and bibliometric analysis. The review was approached using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) coupled with R package involving Biblioshiny, a web interface for Bibliometrix analysis and VOSviewer software analytic tools. Literature searches were conducted in Scopus, Web of Science, and PubMed from the inception through January 21, 2023. Coumarins, depression, coumarin derivatives and treatment were the main search terms used which resulted in the inclusion of 46 eligible publications. Scopoletin, psoralen, 7-hydroxycoumarin, meranzin hydrate, osthole, esculetin/umbelliferone were the most studied coumarins with antidepressant effects. Coumarins and their derivatives exerted antidepressant effects with a stronger affinity for monoamine oxidase-B (MAO-B) inhibition and, their inhibitory effect via neurotransmitter pathway on MAO is well-studied. However, epigenetic modification, neuroendocrine, neurotrophic pathways are understudied. Recent research focuses on their antidepressant effects which targeted cytokines and fibromyalgia. There is a link between the gut microbiome, the brain, and depression; meranzin hydrate exerts an antidepressant activity by remodelling the gastrointestinal system. We established that empirical data on some coumarins and their derivatives to support their antidepressant effects are limited. Likewise, the safe dose range for several coumarins and their derivatives is yet to be fully determined.
Topics: Monoamine Oxidase Inhibitors; Coumarins; Monoamine Oxidase; Antidepressive Agents; Brain
PubMed: 37543158
DOI: 10.1016/j.ejphar.2023.175958 -
Journal of Neural Transmission (Vienna,... Jun 2022Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and... (Review)
Review
Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly.
Topics: Antiparkinson Agents; Dopamine Agents; Humans; Indans; Levodopa; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline
PubMed: 35107654
DOI: 10.1007/s00702-022-02465-w -
Journal of Neural Transmission (Vienna,... Nov 2018Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters and dietary amines. Two pharmacological types with different substrate and... (Review)
Review
Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters and dietary amines. Two pharmacological types with different substrate and inhibitor specificities were reported. Molecular cloning revealed that the two types of MAO were different genes expressed as different proteins with different functions. MAO A and B have identical intron-exon organization derived by duplication of a common ancestral gene thus they are termed isoenzymes. MAO A knockout mice exhibited aggression, the first clear evidence linking genes to behavior. MAO A KO mice exhibited autistic-like behaviors which could be prevented by reducing serotonin levels at an early developmental age (P1-P7) providing potential therapy. MAO B KO mice were non-aggressive and resistant to Parkinsongenic neurotoxin. More recently it was found that MAO A is overexpressed in prostate cancer and correlates with degree of malignancy. The oncogenic mechanism involves a ROS-activated AKT/FOXO1/TWIST1 signaling pathway. Deletion of MAO A reduced prostate cancer stem cells and suppressed invasive adenocarcinoma. MAO A was also overexpressed in classical Hodgkin lymphoma and glioma brain tumors. MAO B was overexpressed in glioma and non-small cell lung cancer. MAO A inhibitors reduce the growth of prostate cancer, drug sensitive and resistant gliomas and classical Hodgkin lymphoma, and enhance standard chemotherapy. Currently, we are developing NIR dye-conjugated clorgyline (MAO A inhibitor) as a novel dual therapeutic/diagnostic agent for cancer. A phase II clinical trial of MAO inhibitor for biochemical recurrent prostate cancer is ongoing. The role of MAO A and B in several cancer types opens new avenues for cancer therapies.
Topics: Animals; Antineoplastic Agents; Behavior; Humans; Isoenzymes; Monoamine Oxidase; Monoamine Oxidase Inhibitors
PubMed: 30259128
DOI: 10.1007/s00702-018-1927-8 -
Cellular and Molecular Neurobiology Jan 2022Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and... (Review)
Review
Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite β-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.
Topics: Animals; Antidepressive Agents; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Phenelzine; Rats; Rats, Sprague-Dawley
PubMed: 33839994
DOI: 10.1007/s10571-021-01078-3 -
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 -
Frontiers in Pharmacology 2019Amphetamine and its derivatives exhibit a wide range of pharmacological activities, including psychostimulant, hallucinogenic, entactogenic, anorectic, or antidepressant... (Review)
Review
Amphetamine and its derivatives exhibit a wide range of pharmacological activities, including psychostimulant, hallucinogenic, entactogenic, anorectic, or antidepressant effects. The mechanisms of action underlying these effects are usually related to the ability of the different amphetamines to interact with diverse monoamine transporters or receptors. Moreover, many of these compounds are also potent and selective monoamine oxidase inhibitors. In the present work, we review how structural modifications on the aromatic ring, the amino group and/or the aliphatic side chain of the parent scaffold, modulate the enzyme inhibitory properties of hundreds of amphetamine derivatives. Furthermore, we discuss how monoamine oxidase inhibition might influence the pharmacology of these compounds.
PubMed: 32038257
DOI: 10.3389/fphar.2019.01590 -
Drug Design, Development and Therapy 2021Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage... (Review)
Review
INTRODUCTION
Parkinson's therapeutic interventions are only symptomatic. An optimal treatment should therefore address the largest number of motor and non-motor symptoms, to manage patients at best. Safinamide is one of the most recent approved drugs for fluctuating patients, in add-on to levodopa, that remains the gold standard treatment. It has a unique mechanism of action, both dopaminergic (as MAO-B inhibitor) and glutamatergic (through Na channel blockade). Results from Phase III trials, post-hoc analyses and real-life experiences suggest a beneficial effect on motor (such as tremor, bradykinesia, rigidity and gait) and non-motor (pain, mood, sleep) symptoms.
AREAS COVERED
Here, the authors discuss clinical efficacy and safety of safinamide, identifying the patients' profiles that could benefit most. A search in PubMed was performed in September 2020, with no time limits. Publications' abstracts were reviewed.
CONCLUSION
Safinamide is peculiar due to its double mechanism of action. Its benefits in improving motor functions and fluctuations, and some non-motor symptoms, could have a valuable impact on patients' quality of life (QoL), together with its safety profile.
Topics: Alanine; Animals; Antiparkinson Agents; Benzylamines; Drug Therapy, Combination; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Quality of Life; Treatment Outcome
PubMed: 34140766
DOI: 10.2147/DDDT.S302673 -
Molecules (Basel, Switzerland) Apr 2022Lung cancer is one of the most common causes of cancer-related deaths worldwide. Monoamine Oxidase-A (MAO-A) enzyme mediates the production of reactive oxygen species...
Lung cancer is one of the most common causes of cancer-related deaths worldwide. Monoamine Oxidase-A (MAO-A) enzyme mediates the production of reactive oxygen species (ROS) that trigger DNA damage and oxidative injury of cells resulting in tumor initiation and progression. Available MAO-A inhibitors are used as antidepressants, however, their role as anticancer agents is still under investigation. Ligand- and structure-based drug design approaches guided the discovery and development of novel MAO-A inhibitors. A series of 1H indole-2-carboxamide derivatives was prepared and characterized using 1H-NMR, 13C-NMR, and IR. The antiproliferative effects of MAO-A inhibitors were evaluated using the cell viability assay (MTT), and MAO-A activity was evaluated using MAO-A activity assay. The presumed inhibitors significantly inhibited the growth of lung cell lines in a dose- and time dependent manner. The half maximal inhibitory concentration (IC) values of MAO-A inhibitors ( and ) were 33.37, 146.1, 208.99, 307.7, and 147.2 µM, respectively, in A549. Glide docking against MAO-A showed that the derivatives accommodate MAO-A binding cleft and engage with key binding residues. MAO-A inhibitors provide significant and consistent evidence on MAO-A activity in lung cancer and present a potential target for the development of new chemotherapeutic agents.
Topics: Antidepressive Agents; Antineoplastic Agents; Humans; Lung Neoplasms; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 35566238
DOI: 10.3390/molecules27092887 -
The Cochrane Database of Systematic... Feb 2018Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated.... (Review)
Review
BACKGROUND
Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects.
OBJECTIVES
To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults.
SEARCH METHODS
We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries.
SELECTION CRITERIA
Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain.
DATA COLLECTION AND ANALYSIS
From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table.
MAIN RESULTS
We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache.
AUTHORS' CONCLUSIONS
There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.
Topics: 5-Hydroxytryptophan; Acetaminophen; Adult; Amitriptyline; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Benzodiazepines; Carisoprodol; Drug Therapy, Combination; Duloxetine Hydrochloride; Fibromyalgia; Fluoxetine; Humans; Magnesium; Malates; Melatonin; Monoamine Oxidase Inhibitors; Muscle Relaxants, Central; Pregabalin; Randomized Controlled Trials as Topic
PubMed: 29457627
DOI: 10.1002/14651858.CD010585.pub2