Evaluation of Selected Natural Compounds as Dual Inhibitors of Catechol-O-Methyltransferase and Monoamine Oxidase

2019 ◽  
Vol 19 (2) ◽  
pp. 133-145 ◽  
Author(s):  
Idalet Engelbrecht ◽  
Jacobus P. Petzer ◽  
Anél Petzer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Monoamine Oxidase ◽  
Symptomatic Treatment ◽  
Natural Compounds ◽  
Comt Inhibition ◽  
Comt Inhibitors ◽  
Mao B ◽  
Dual Inhibitors

Background: The most effective symptomatic treatment of Parkinson’s disease remains the metabolic precursor of dopamine, L-dopa. To enhance the efficacy of L-dopa, it is often combined with inhibitors of the enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) B, key metabolic enzymes of L-dopa and dopamine. Objective: This study attempted to discover compounds that exhibit dual inhibition of COMT and MAO-B among a library of 40 structurally diverse natural compounds. Such dual acting inhibitors may be effective as adjuncts to L-dopa and offer enhanced value in the management of Parkinson’s disease. Methods: Selected natural compounds were evaluated as in vitro inhibitors of rat liver COMT and recombinant human MAO. Reversibility of MAO inhibition was investigated by dialysis. Results: Among the natural compounds morin (IC50 = 1.32 µM), chlorogenic acid (IC50 = 6.17 µM), (+)-catechin (IC50 = 0.86 µM), alizarin (IC50 = 0.88 µM), fisetin (IC50 = 5.78 µM) and rutin (IC50 = 25.3 µM) exhibited COMT inhibition. Among these active COMT inhibitors only morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM) and fisetin (IC50 = 7.33 µM) were noteworthy MAO inhibitors, with specificity for MAO-A. Conclusion: None of the natural products investigated here are dual COMT/MAO-B inhibitors. However, good potency COMT inhibitors have been identified, which may serve as leads for future development of COMT inhibitors.

scholarly journals Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson’s Disease: Past, Present, and Future

2021 ◽  
pp. 1-17
Author(s):  
Yu-Yan Tan ◽  
Peter Jenner ◽  
Sheng-Di Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Monoamine Oxidase ◽  
Early Stage ◽  
Symptomatic Treatment ◽  
Monoamine Oxidase B ◽  
Motor Symptoms ◽  
Mao B ◽  
Advanced Stages ◽  
Non Motor Symptoms

Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson’s disease (PD). MAO-B inhibitor monotherapy has been shown to be effective and safe for the treatment of early-stage PD, while MAO-B inhibitors as adjuvant drugs have been widely applied for the treatment of the advanced stages of the illness. MAO-B inhibitors can effectively improve patients’ motor and non-motor symptoms, reduce “OFF” time, and may potentially prevent/delay disease progression. In this review, we discuss the effects of MAO-B inhibitors on motor and non-motor symptoms in PD patients, their mechanism of action, and the future development of MAO-B inhibitor therapy.

▼ Safinamide for Parkinson’s disease

2018 ◽  
Vol 56 (5) ◽  
pp. 54-57
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Monoamine Oxidase ◽  
Motor Fluctuations ◽  
Daily Activities ◽  
Monoamine Oxidase B ◽  
Motor Symptoms ◽  
Idiopathic Parkinson’S Disease ◽  
Mao B ◽  
Idiopathic Parkinson's Disease

▼ Safinamide (Xadago - Zambon S.p.A) is a monoamine-oxidase B (MAO-B) inhibitor licensed as add-on therapy for people with idiopathic Parkinson’s disease who are experiencing motor fluctuations with levodopa.1 Currently there is no cure for Parkinson’s disease and drugs are used to reduce motor symptoms and improve daily activities.2,3 Here, we review the evidence for this MAO-B inhibitor.

scholarly journals Comparative effectiveness of dopamine agonists and monoamine oxidase type-B inhibitors for Parkinson’s disease: a multiple treatment comparison meta-analysis

2020 ◽  
Vol 76 (12) ◽  
pp. 1731-1743
Author(s):  
Caroline D. Binde ◽  
Ingunn F. Tvete ◽  
Jørund I. Gåsemyr ◽  
Bent Natvig ◽  
Marianne Klemp
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Monoamine Oxidase ◽  
Comparative Effectiveness ◽  
Dopamine Agonists ◽  
Relative Effectiveness ◽  
Type B ◽  
Mao B ◽  
Treatment Comparison ◽  
Monoamine Oxidase Type B

Abstract Purpose To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson’s disease. Methods We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson’s disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson’s Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. Results Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. Conclusions Dopamine agonists were found to be effective as treatment for Parkinson’s disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson’s disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.

Monoamine oxidase B (MAO B) inhibitor therapy in Parkinson's disease: The degree and reversibility of human brain MAO B inhibition by Ro 19 6327

Neurology ◽  
1993 ◽  
Vol 43 (10) ◽  
pp. 1984-1984 ◽  
Author(s):  
J. S. Fowler ◽  
N. D. Volkow ◽  
J. Logan ◽  
D. J. Schlyer ◽  
R. R. MacGregor ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Monoamine Oxidase ◽  
Human Brain ◽  
Inhibitor Therapy ◽  
Monoamine Oxidase B ◽  
Mao B

Parkinson’s Disease: A Review from Pathophysiology to Treatment

2020 ◽  
Vol 20 (9) ◽  
pp. 754-767 ◽  
Author(s):  
Bianca L.B. Marino ◽  
Lucilene R. de Souza ◽  
Kessia P.A. Sousa ◽  
Jaderson V. Ferreira ◽  
Elias C. Padilha ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Elderly Population ◽  
Functional Performance ◽  
Synaptic Cleft ◽  
The Elderly ◽  
Functional Mobility ◽  
Comt Inhibitors ◽  
Mao B ◽  
Physical Limitations

: Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.

Molecular simulation studies of Alpha Pinene, an alkene in search for oxidative stress targeted therapeutic paradigms for the treatment of Parkinson’s disease: A computational approach and its in-vitro antioxidant validation

2021 ◽  
Vol 18 ◽  
Author(s):  
Rajnish Srivastava ◽  
Pratim Kumar Choudhury ◽  
Suresh Kumar Dev ◽  
Vaibhav Rathore
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Energy ◽  
Molecular Interaction ◽  
Hypochlorous Acid ◽  
Cell Degeneration ◽  
Mao B ◽  
Alpha Pinene

Aim: The present study was expected to explore the molecular interaction of five oxidative stress (OS) associated target receptors with Alpha-Pinene and its antioxidant validation for the effective treatment of Parkinson’s disease (PD). Background: Oxidative stress (OS) via multitudinous cascades is considered to be the leading attribute to dopaminergic cell degeneration in PD. Furthermore, it is also well-linked to other mechanisms involved in the neurodegeneration process, like dysfunction of mitochondria, neuroinflammation and excitotoxicity due to NO. Objective: The present investigation was to establish a molecular association of OS-associated target receptors with the bioactive compound alpha-pinene and how this molecular interaction empowers the mitigation of PD. Material and Method: Five different molecular targets namely Peroxisome Proliferator-Activated Receptor- Gamma (PPARγ), Liver-X receptor beta (LXR- β), Human Monoamine Oxidase-B (MAO-B), Human Nuclear receptor related-1 protein (Nurr1) and Human Lipoprotein-associated phospholipase A2 (Lp-PLA2) were obtained from RCSB-PDB, which has some leading association in the inhibition of the OS-induced neurodegeneration. Molecular interactions were stuffed by the simulation molecular docking software. Antioxidant activity was validated by in-vitro models as per standardized procedures against 2,2- diphenyl-1- picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline -6-sulfonic acid) (ABTS), Ferric ion (Fe3+), Hydroxyl (•OH), nitric oxide (•NO), Peroxynitrite (ONOO-) and Hypochlorous acid (HOCl). Result: Our results indicated that alpha-pinene can interact with all the five different target receptors at the active binding site of receptors. Alpha-pinene was found to show better interaction with MAO-B, Nurr1 and PPARγ with binding energy of -5.50, -4.52 and -5.25, respectively as compared to the native ligand. Furthermore, the interaction of alpha-pinene with LXR-β and Lp-PLA2 was also significant with binding energy of -5.6 and -5.12, respectively. It also capable of neutralizing all the different free radicals under consideration with significant IC50 values against HOCl and •NO. Conclusion: It might be concluded that alpha-pinene could act as a potential inhibitor and scavenger of OS which could act on the multiple target receptors under consideration.

scholarly journals Study of Monoamine Oxidase-B and Indole Derivatives Using Two Molecular Docking Programs: Molegro and MOE

2020 ◽  
Vol 8 (09) ◽  
pp. 25-31
Author(s):  
W. Soufi ◽  
M. Merad ◽  
F. BOUKLI Hacene ◽  
S. Ghalem
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
Monoamine Oxidase ◽  
Indole Derivatives ◽  
Modeling Tools ◽  
Molegro Virtual Docker ◽  
Mao B ◽  
Modeling Methods

Inhibition of the enzyme Monoamine oxidase (MAO) is an important approach in the treatment of Parkinson’s disease. A series of indole derivatives were synthesised and evaluated as inhibitors of MAO-B may give insight to develop new ways of antiparkinson drug, In general, the derivatives were found to be selective MAO-B inhibitors with IC50 values . MAO-B inhibitors,  are considered useful in the therapy of Parkinson’s disease since oxidation by MAO-B represents a major catabolic pathway of dopamine in the central nervous system .                      Our goal of research is to study the inhibition of MAO-B by molecular modeling methods. Different molecular modeling tools are used to perform this work (molecular mechanics, molecular dynamics and molecular docking by two programms MDV ( molegro virtual docker) and MOE (modelling Opering Environment. The results obtained from this work, into which the inhibition of MAO-B by molecular modeling methods was elucidated, allow us to conclude that indole derivatives are promising reversible MAO-B inhibitors with a possible role in the treatment of neurodegenerative diseases such as Parkinson’s disease (PD). 

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