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Advances in Therapy May 2022Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the... (Review)
Review
Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the pros and cons of initiating treatment with levodopa-sparing strategies. The current drive toward early levodopa monotherapy is primarily driven by safety and tolerability concerns with dopamine agonists and only mild efficacy of other available approaches. Recently, P2B001, a novel once-daily combination of low-dose, extended-release formulations of pramipexole and rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this drug evaluation, we review the preclinical and current clinical data for P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.
Topics: Humans; Indans; Levodopa; Parkinson Disease; Pramipexole
PubMed: 35267155
DOI: 10.1007/s12325-022-02097-2 -
Drug Design, Development and Therapy 2020Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable...
BACKGROUND
Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors.
METHODS
The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results.
RESULTS
-(2,4-Dinitrophenyl)benzo[][1,3]dioxole-5-carboxamide (, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC = 56 nM, K = 6.3 nM), while -(2,4-dinitrophenyl)benzamide (, ST-2023) showed higher preference for MAO A (IC = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites.
CONCLUSION
The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.
Topics: Anilides; Dose-Response Relationship, Drug; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 32099324
DOI: 10.2147/DDDT.S236586 -
Journal of Enzyme Inhibition and... Dec 2023Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that...
Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional "one-target, one-molecule" approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H receptor ligands (HR). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative displayed a value of 0.012 μM. The multitargeting potential of these HR ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a value of 0.036 μM at HR and IC values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound can be a lead structure for developing new multi-targeting anti-AD agents.
Topics: Humans; Alzheimer Disease; Structure-Activity Relationship; Cholinesterase Inhibitors; Acetylcholinesterase; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Benzothiazoles; Ligands
PubMed: 36789662
DOI: 10.1080/14756366.2023.2175821 -
Nutrients Sep 2022leaves contain a variety of phytoestrogens, including flavonoids, isoflavonoids, and coumestan derivatives. In this study, we aimed to identify the active ingredients...
leaves contain a variety of phytoestrogens, including flavonoids, isoflavonoids, and coumestan derivatives. In this study, we aimed to identify the active ingredients of leaves and to elucidate their function in monoamine oxidase (MAO) activation and Aβ self-aggregation using in vitro and in silico approaches. To the best of our knowledge, this is the first study to elucidate coumestrol as a selective and competitive MAO-A inhibitor. We identified that coumestrol, a coumestan-derivative, exhibited a selective inhibitory effect against MAO-A (IC = 1.99 ± 0.68 µM), a key target protein for depression. In a kinetics analysis with 0.5 µg MAO-A, 40-160 µM substrate, and 25 °C reaction conditions, coumestrol acts as a competitive MAO-A inhibitor with an inhibition constant of 1.32 µM. During an in silico molecular docking analysis, coumestrol formed hydrogen bonds with FAD and pi-pi bonds with hydrophobic residues at the active site of the enzyme. Moreover, based on thioflavin-T-based fluorometric assays, we elucidated that coumestrol effectively prevented self-aggregation of amyloid beta (Aβ), which induces an inflammatory response in the central nervous system (CNS) and is a major cause of Alzheimer's disease (AD). Therefore, coumestrol could be used as a CNS drug to prevent diseases such as depression and AD by the inhibition of MAO-A and Aβ self-aggregation.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Coumestrol; Flavin-Adenine Dinucleotide; Flavonoids; Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Phytoestrogens; Structure-Activity Relationship
PubMed: 36145197
DOI: 10.3390/nu14183822 -
Antioxidants (Basel, Switzerland) Oct 2021Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B...
Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson's disease (PD). Herein, 24 melatonin analogues (-) were synthesized as novel MAO-B inhibitors with the potential to counteract oxidative stress in neuronal PC12 cells. Structure elucidation, characterization, and purity of the synthesized compounds were performed using H-NMR, C-NMR, HRMS, and HPLC. At 10 µM, 12 compounds showed >50% MAO-B inhibition. Among them, compounds , , and - showed >70% inhibition of MAO-B and IC values of 1.41, 0.91, 1.20, 0.66, and 2.41 µM, respectively. When compared with the modest selectivity index of rasagiline (, a well-known MAO-B inhibitor, SI > 50), compounds , and demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively). Furthermore, compounds and exhibited safe neurotoxicity profiles in PC12 cells and reversed 6-OHDA- and rotenone-induced neuronal oxidative stress. Both compounds significantly up-regulated the expression of the anti-oxidant enzyme, heme oxygenase (HO)-1. Treatment with Zn(II)-protoporphyrin IX (ZnPP), a selective HO-1 inhibitor, abolished the neuroprotective effects of the tested compounds, suggesting a critical role of HO-1 up-regulation. Both compounds increased the nuclear translocation of Nrf2, which is a key regulator of the antioxidative response. Taken together, these data show that compounds and could be further exploited for their multi-targeted role in oxidative stress-related PD therapy.
PubMed: 34679739
DOI: 10.3390/antiox10101604 -
Oncotarget Mar 2016Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective...
Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis.
Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Cell Proliferation; Dacarbazine; Disease Progression; Drug Resistance, Neoplasm; Drug Synergism; Glioma; Humans; Male; Mice; Mice, Nude; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Temozolomide; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 26871599
DOI: 10.18632/oncotarget.7283 -
Journal of Neurochemistry Oct 2016Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain... (Review)
Review
Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed. Alternatively, the patient is offered deep brain stimulation of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials, and some of them already yielding positive results in phase 3 trials. In addition, non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia, including adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) and modulators of the metabolic glutamate receptor 5 (mGluR5 - mavoglurant) and serotonin (eltoprazine) receptors. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, inosine (a precursor of urate), and isradipine (a dihydropyridine calcium channel blocker), as well as active and passive immunization against α-synuclein and inhibitors or modulators of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available. We here review the current status of treatment options for motor and non-motor symptoms, and discuss current investigative strategies for disease modification. This review provides basic insights, mainly addressing basic scientists and non-specialists. It stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials. Non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine - a dihydropyridine calcium channel blocker - as well as active and passive immunization against α-synuclein and inhibitors of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non-motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. This article is part of a special issue on Parkinson disease.
Topics: Animals; Antiparkinson Agents; Catechol O-Methyltransferase; Clinical Trials as Topic; Deep Brain Stimulation; Dopamine Agonists; Humans; Immunotherapy; Levodopa; Monoamine Oxidase Inhibitors; Neurosciences; Parkinson Disease; Subthalamic Nucleus; Treatment Outcome
PubMed: 27577098
DOI: 10.1111/jnc.13750 -
The Cochrane Database of Systematic... Oct 2017Recognition is growing that social anxiety disorder (SAnD) is a chronic and disabling disorder, and data from early trials demonstrate that medication may be effective... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recognition is growing that social anxiety disorder (SAnD) is a chronic and disabling disorder, and data from early trials demonstrate that medication may be effective in its treatment. This systematic review is an update of an earlier review of pharmacotherapy of SAnD.
OBJECTIVES
To assess the effects of pharmacotherapy for social anxiety disorder in adults and identify which factors (methodological or clinical) predict response to treatment.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR-Studies and CCMDCTR-References) to 17 August 2015. The CCMDCTR contains reports of relevant RCTs from MEDLINE (1950-), Embase (1974-), PsycINFO (1967-) and CENTRAL (all years). We scanned the reference lists of articles for additional studies. We updated the search in August 2017 and placed additional studies in Awaiting Classification, these will be incorporated in the next version of the review, as appropriate.
SELECTION CRITERIA
We restricted studies to randomised controlled trials (RCTs) of pharmacotherapy versus placebo in the treatment of SAnD in adults.
DATA COLLECTION AND ANALYSIS
Two authors (TW and JI) assessed trials for eligibility and inclusion for this review update. We extracted descriptive, methodological and outcome information from each trial, contacting investigators for missing information where necessary. We calculated summary statistics for continuous and dichotomous variables (if provided) and undertook subgroup and sensitivity analyses.
MAIN RESULTS
We included 66 RCTs in the review (> 24 weeks; 11,597 participants; age range 18 to 70 years) and 63 in the meta-analysis. For the primary outcome of treatment response, we found very low-quality evidence of treatment response for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (number of studies (k) = 24, risk ratio (RR) 1.65; 95% confidence interval (CI) 1.48 to 1.85, N = 4984). On this outcome there was also evidence of benefit for monoamine oxidase inhibitors (MAOIs) (k = 4, RR 2.36; 95% CI 1.48 to 3.75, N = 235), reversible inhibitors of monoamine oxidase A (RIMAs) (k = 8, RR 1.83; 95% CI 1.32 to 2.55, N = 1270), and the benzodiazepines (k = 2, RR 4.03; 95% CI 2.45 to 6.65, N = 132), although the evidence was low quality. We also found clinical response for the anticonvulsants with gamma-amino butyric acid (GABA) analogues (k = 3, RR 1.60; 95% CI 1.16 to 2.20, N = 532; moderate-quality evidence). The SSRIs were the only medication proving effective in reducing relapse based on moderate-quality evidence. We assessed tolerability of SSRIs and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine on the basis of treatment withdrawal; this was higher for medication than placebo (SSRIs: k = 24, RR 2.59; 95% CI 1.97 to 3.39, N = 5131, low-quality evidence; venlafaxine: k = 4, RR 3.23; 95% CI 2.15 to 4.86, N = 1213, moderate-quality evidence), but there were low absolute rates of withdrawal for both these medications classes compared to placebo. We did not find evidence of a benefit for the rest of the medications compared to placebo.For the secondary outcome of SAnD symptom severity, there was benefit for the SSRIs, the SNRI venlafaxine, MAOIs, RIMAs, benzodiazepines, the antipsychotic olanzapine, and the noradrenergic and specific serotonergic antidepressant (NaSSA) atomoxetine in the reduction of SAnD symptoms, but most of the evidence was of very low quality. Treatment with SSRIs and RIMAs was also associated with a reduction in depression symptoms. The SSRIs were the only medication class that demonstrated evidence of reduction in disability across a number of domains.We observed a response to long-term treatment with medication for the SSRIs (low-quality evidence), for the MAOIs (very low-quality evidence) and for the RIMAs (moderate-quality evidence).
AUTHORS' CONCLUSIONS
We found evidence of treatment efficacy for the SSRIs, but it is based on very low- to moderate-quality evidence. Tolerability of SSRIs was lower than placebo, but absolute withdrawal rates were low.While a small number of trials did report treatment efficacy for benzodiazepines, anticonvulsants, MAOIs, and RIMAs, readers should consider this finding in the context of potential for abuse or unfavourable side effects.
Topics: Adult; Aged; Anticonvulsants; Chronic Disease; Humans; Middle Aged; Monoamine Oxidase Inhibitors; Phobia, Social; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Venlafaxine Hydrochloride; Young Adult
PubMed: 29048739
DOI: 10.1002/14651858.CD001206.pub3 -
Molecules (Basel, Switzerland) Jan 2019Monoamine oxidase inhibitions are considered as important targets for the treatment of depression, anxiety, and neurodegenerative disorders, including Alzheimer's and... (Review)
Review
Monoamine oxidase inhibitions are considered as important targets for the treatment of depression, anxiety, and neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. This has encouraged many medicinal chemistry research groups for the development of most promising selective monoamine oxidase (MAO) inhibitors. A large number of plant isolates also reported for significant MAO inhibition potential in recent years. Differently substituted flavonoids have been prepared and investigated as MAO-A and MAO-B inhibitors. Flavonoid scaffold showed notable antidepressant and neuroprotective properties as revealed by various and established preclinical trials. The current review made an attempt to summarizing and critically evaluating the new findings on the quercetin and related flavonoid derivatives functions as potent MAO isoform inhibitors.
Topics: Animals; Chemical Phenomena; Flavonoids; Humans; Mental Disorders; Models, Molecular; Monoamine Oxidase Inhibitors; Nervous System Diseases; Quercetin; Structure-Activity Relationship
PubMed: 30678358
DOI: 10.3390/molecules24030418 -
Experimental & Molecular Medicine Jul 2021Monoamine oxidase (MAO) is believed to mediate the degradation of monoamine neurotransmitters, including dopamine, in the brain. Between the two types of MAO, MAO-B has...
Monoamine oxidase (MAO) is believed to mediate the degradation of monoamine neurotransmitters, including dopamine, in the brain. Between the two types of MAO, MAO-B has been believed to be involved in dopamine degradation, which supports the idea that the therapeutic efficacy of MAO-B inhibitors in Parkinson's disease can be attributed to an increase in extracellular dopamine concentration. However, this belief has been controversial. Here, by utilizing in vivo phasic and basal electrochemical monitoring of extracellular dopamine with fast-scan cyclic voltammetry and multiple-cyclic square wave voltammetry and ex vivo fluorescence imaging of dopamine with GRAB, we demonstrate that MAO-A, but not MAO-B, mainly contributes to striatal dopamine degradation. In contrast, our whole-cell patch-clamp results demonstrated that MAO-B, but not MAO-A, was responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum. We conclude that, in contrast to the traditional belief, MAO-A and MAO-B have profoundly different roles: MAO-A regulates dopamine levels, whereas MAO-B controls tonic GABA levels.
Topics: Animals; Clorgyline; Corpus Striatum; Dopamine; Female; Male; Mice, Inbred C57BL; Molecular Imaging; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Patch-Clamp Techniques; Rats, Sprague-Dawley; Selegiline; gamma-Aminobutyric Acid; Mice; Rats
PubMed: 34244591
DOI: 10.1038/s12276-021-00646-3