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Scientific Reports Nov 2023Monoamine oxidase B (MAO-B) inhibitors are used to control Parkinson's disease (PD). Selegiline, rasagiline, and safinamide are widely used as MAO-B inhibitors...
Monoamine oxidase B (MAO-B) inhibitors are used to control Parkinson's disease (PD). Selegiline, rasagiline, and safinamide are widely used as MAO-B inhibitors worldwide. Although these drugs inhibit MAO-B, there are pharmacological and chemical differences, such as the inhibitory activity, the non-dopaminergic properties in safinamide, and the amphetamine-like structure in selegiline. MAO-B inhibitors may differ in adverse events (AEs). However, differences in actual practical clinics are not fully investigated. A retrospective study was conducted using FAERS, the largest database of spontaneous adverse events. AE signals for MAO-B inhibitors, including selegiline, rasagiline, and safinamide, were detected using the reporting odds ratio method and compared. Hypocomplementemia, hepatic cyst, hepatic function abnormal, liver disorder and cholangitis were detected for selegiline as drug-specific signals. The amphetamine effect was not confirmed for any of the three MAO-B inhibitors. The tyramine reaction was detected as an AE signal only for rasagiline. Moreover, the REM sleep behavior disorder was not detected as an AE signal for safinamide, suggesting that non-dopaminergic effects might be beneficial. Considering the differences in AEs for MAO-B inhibitors will assist with the appropriate PD medication.
Topics: Humans; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline; Retrospective Studies; Monoamine Oxidase; Dopamine Agents; Amphetamines
PubMed: 37935702
DOI: 10.1038/s41598-023-44142-2 -
Journal of Enzyme Inhibition and... Dec 2023Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three... (Review)
Review
Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided.
Topics: Humans; Monoamine Oxidase; Acetylcholinesterase; Alzheimer Disease; Monoamine Oxidase Inhibitors; Molecular Docking Simulation; Cholinesterase Inhibitors; Structure-Activity Relationship
PubMed: 37955252
DOI: 10.1080/14756366.2023.2270781 -
Molecules (Basel, Switzerland) Jun 2023With the significant growth of patients suffering from neurodegenerative diseases (NDs), novel classes of compounds targeting monoamine oxidase type B (MAO-B) are... (Review)
Review
With the significant growth of patients suffering from neurodegenerative diseases (NDs), novel classes of compounds targeting monoamine oxidase type B (MAO-B) are promptly emerging as distinguished structures for the treatment of the latter. As a promising function of computer-aided drug design (CADD), structure-based virtual screening (SBVS) is being heavily applied in processes of drug discovery and development. The utilization of molecular docking, as a helping tool for SBVS, is providing essential data about the poses and the occurring interactions between ligands and target molecules. The current work presents a brief discussion of the role of MAOs in the treatment of NDs, insight into the advantages and drawbacks of docking simulations and docking software, and a look into the active sites of MAO-A and MAO-B and their main characteristics. Thereafter, we report new chemical classes of MAO-B inhibitors and the essential fragments required for stable interactions focusing mainly on papers published in the last five years. The reviewed cases are separated into several chemically distinct groups. Moreover, a modest table for rapid revision of the revised works including the structures of the reported inhibitors together with the utilized docking software and the PDB codes of the crystal targets applied in each study is provided. Our work could be beneficial for further investigations in the search for novel, effective, and selective MAO-B inhibitors.
Topics: Humans; Monoamine Oxidase Inhibitors; Molecular Docking Simulation; Monoamine Oxidase; Drug Discovery; Drug Design; Structure-Activity Relationship
PubMed: 37375370
DOI: 10.3390/molecules28124814 -
Diabetes, Obesity & Metabolism Sep 2016β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate... (Review)
Review
β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field. In this review, we discuss recent studies reporting successful human β-cell proliferation including WS6, an IkB kinase and EBP1 inhibitor; harmine and 5-IT, both DYRK1A inhibitors; GNF7156 and GNF4877, GSK-3β and DYRK1A inhibitors; osteoprotegrin and Denosmab, receptor activator of NF-kB (RANK) inhibitors; and SerpinB1, a protease inhibitor. These studies provide important examples of proteins and pathways that may prove useful for designing therapeutic strategies to counter the different forms of human diabetes.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Proliferation; Denosumab; Diabetes Mellitus; Glycogen Synthase Kinase 3 beta; Harmine; Humans; I-kappa B Kinase; Insulin-Secreting Cells; Monoamine Oxidase Inhibitors; Osteoprotegerin; Phenylurea Compounds; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; RNA-Binding Proteins; Receptor Activator of Nuclear Factor-kappa B; Serine Proteinase Inhibitors; Serpins; Tryptamines; Dyrk Kinases
PubMed: 27615134
DOI: 10.1111/dom.12731 -
ACS Omega Oct 2023The monoamine oxidase enzyme (MAO), which is bound on the membrane of mitochondria, catalyzes the oxidative deamination of endogenous and exogenous monoamines, including... (Review)
Review
The monoamine oxidase enzyme (MAO), which is bound on the membrane of mitochondria, catalyzes the oxidative deamination of endogenous and exogenous monoamines, including monoamine neurotransmitters such as serotonin, adrenaline, and dopamine. These enzymes have been proven to play a significant role in neurodegeneration; thus, they have recently been researched as prospective therapeutic targets for neurodegenerative illness treatment and management. MAO inhibitors have already been marketed as neurodegeneration illness treatments despite their substantial side effects. Hence, researchers are concentrating on developing novel molecules with selective and reversible inhibitory properties. Piperine, which is a phytochemical component present in black pepper, has been established as a potent MAO inhibitor. Piperine encompasses a piperidine nucleus with antibacterial, anti-inflammatory, antihypertensive, anticonvulsant, antimalarial, antiviral, and anticancer properties. The current Review focuses on the structural changes and structure-activity relationships of piperidine derivatives as MAO inhibitors.
PubMed: 37867639
DOI: 10.1021/acsomega.3c05883 -
Molecules (Basel, Switzerland) Dec 2016This Special Issue, entitled "Molecules against Alzheimer", gathers a number of original articles, short communications, and review articles on recent research efforts...
This Special Issue, entitled "Molecules against Alzheimer", gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, β-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Drug Discovery; Humans; Mitochondria; Molecular Targeted Therapy; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Oxidative Stress; Wnt Signaling Pathway
PubMed: 27999295
DOI: 10.3390/molecules21121736 -
Cureus Aug 2022Parkinson's disease (PD) is a progressive neurodegenerative age-related disorder that affects the central nervous system (CNS) and is characterized by uncontrollable... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative age-related disorder that affects the central nervous system (CNS) and is characterized by uncontrollable movements such as shaking, stiffness, and loss of balance and coordination. Depression is a common non-motor manifestation of PD, but unfortunately, depression remains unrecognized and often undertreated. The underlying pathophysiology of depression in PD is complicated, and many studies have been conducted to know the exact cause, but the question remains unanswered. In this article, we discuss various pathophysiologies by which depression occurs in PD. The most widely accepted theories are neuroinflammation and monoamine oxidase theory. This article also explored the pharmacological treatment of depression in PD; this involves standard antidepressant therapy such as tricyclic antidepressants (TCA), serotonin-norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), and monoamine oxidase inhibitors (MAO); non-pharmacological treatments such as electroconvulsive therapy (ECT), cognitive-behavioral therapy (CBT) have also been discussed. However, physicians hesitate to prescribe antidepressants to patients with PD due to concerns about harmful drug-drug interactions between antidepressants and antiparkinsonian drugs. Despite the complicated link between PD and depression, the co-administration of antidepressants and antiparkinsonian drugs is safe and beneficial when appropriately managed. However, early recognition and initiation of treatment of depression in PD reduces the longitudinal course and improves the cross-sectional picture. This review article also explored the clinical and diagnostic findings and impact on the quality of life of depression in PD.
PubMed: 36106206
DOI: 10.7759/cureus.27750 -
Experimental & Molecular Medicine Aug 2022Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation and the destruction of joints and systemic organs. RA is commonly accompanied...
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation and the destruction of joints and systemic organs. RA is commonly accompanied by neuropsychiatric complications, such as cognitive impairment and depression. However, the role of monoamine oxidase (MAO) and its inhibitors in controlling neurotransmitters associated with these complications in RA have not been clearly identified. Here, we report that peripheral and central MAO-B are highly associated with joint inflammation and cognitive impairment in RA, respectively. Ribonucleic acid (RNA) sequencing and protein expression quantification were used to show that MAO-B and related molecules, such as gamma aminobutyric acid (GABA), were elevated in the inflamed synovium of RA patients. In primary cultured fibroblast-like synoviocytes in the RA synovium, MAO-B expression was significantly increased by tumor necrosis factor (TNF)-α-induced autophagy, which produces putrescine, the polyamine substrate for GABA synthesis. We also observed that MAO-B-mediated aberrant astrocytic production of GABA was augmented by interleukin (IL)-1β and inhibited CA1-hippocampal pyramidal neurons, which are responsible for memory storage, in an animal model of RA. Moreover, a newly developed reversible inhibitor of MAO-B ameliorated joint inflammation by inhibiting cyclooxygenase (Cox)-2. Therefore, MAO-B can be an effective therapeutic target for joint inflammation and cognitive impairment in patients with RA.
Topics: Animals; Arthritis, Rheumatoid; Cells, Cultured; Cognitive Dysfunction; Fibroblasts; Inflammation; Monoamine Oxidase; Tumor Necrosis Factor-alpha; gamma-Aminobutyric Acid
PubMed: 35982301
DOI: 10.1038/s12276-022-00830-z -
Frontiers in Neuroscience 2016HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to... (Review)
Review
HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases. Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to "dirty drugs" for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress toward strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent metabolism of MTDLs.
PubMed: 27597816
DOI: 10.3389/fnins.2016.00375 -
Biomolecules Oct 2022Alzheimer's disease (AD) is the most common type of dementia and is a serious disruption to normal life. Monoamine oxidase-B (MAO-B) is an important target for the...
Alzheimer's disease (AD) is the most common type of dementia and is a serious disruption to normal life. Monoamine oxidase-B (MAO-B) is an important target for the treatment of AD. In this study, machine learning approaches were applied to investigate the identification model of MAO-B inhibitors. The results showed that the identification model for MAO-B inhibitors with K-nearest neighbor(KNN) algorithm had a prediction accuracy of 94.1% and 88.0% for the 10-fold cross-validation test and the independent test set, respectively. Secondly, a quantitative activity prediction model for MAO-B was investigated with the Topomer CoMFA model. Two separate cutting mode approaches were used to predict the activity of MAO-B inhibitors. The results showed that the cut model with q = 0.612 (cross-validated correlation coefficient) and r = 0.824 (non-cross-validated correlation coefficient) were determined for the training and test sets, respectively. In addition, molecular docking was employed to analyze the interaction between MAO-B and inhibitors. Finally, based on our proposed prediction model, 1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)propan-1-one (LB) was predicted as a potential MAO-B inhibitor and was validated by a multi-spectroscopic approach including fluorescence spectra and ultraviolet spectrophotometry.
Topics: Humans; Molecular Docking Simulation; Monoamine Oxidase Inhibitors; Monoamine Oxidase; Spectrum Analysis; Alzheimer Disease; Machine Learning
PubMed: 36291679
DOI: 10.3390/biom12101470