MAOIs Research Articles

Selegiline reduces daytime sleepiness in patients with Parkinson's disease

ObjectivesExcessive daytime sleepiness (EDS) affects a large percentage of Parkinson's disease (PD) patients, and it is enhanced by dopamine agonist drugs. Currently, there is no treatment of choice for EDS in PD. Our aim was to check the clinical impression that some patients who were given selegiline, a selective inhibitor of monoamine oxidase B, experienced an improvement in their daytime somnolence.MethodsIn the present study, we retrospectively identified 45 Parkinson's disease patients (21 females and 24 males) among those referred to the PD Center in Varese that (a) showed excessive daytime sleepiness, usually developed after the introduction of a dopamine agonist, (b) were given selegiline 10 mg to improve their treatment schedule independently of excessive sleepiness, and (c) in whom the Epworth Sleepiness Scale (ESS) and the Parkinson's Disease Sleep Scale (PDSS) scores were available both before and 3 months after the introduction of selegiline.ResultsWe compared the corresponding scores (ESS, PDSS, and UPDRS III) evaluated before and 3 months after the introduction of selegiline by the nonparametric Mann–Whitney U test: The differences showed a statistically significant improvement of somnolence but no change in the UPDRS III scores.ConclusionDespite some limitations, our data suggest that selegiline may be a valuable add‐on therapy in PD patients to reduce their daytime somnolence.

New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors

Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N'-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 μM, Selectivity Index (SI): 9.70 × 10-4), 7 (0.009 μM, SI: 4.55 × 10-5), 14 (0.001 μM, SI: 8.00 × 10-4), 21 (0.009 μM, SI: 1.37 × 10-5), and 42 (0.010 μM, SI: 5.40 × 10-6), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.

Acute and chronic treatment with moclobemide, a reversible MAO-inhibitor, potentiates the antielectroshock activity of conventional antiepileptic drugs in mice

BackgroundDue to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin. MethodsThe effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. ResultsGiven acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5‐75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment. ConclusionsAcute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards.

Evaluation of the combined activity of benzimidazole arylhydrazones as new anti-Parkinsonian agents: monoamine oxidase-B inhibition, neuroprotection and oxidative stress modulation.

Neuroprotective drugs and selective monoamine oxidase inhibitors can slow down the progression and improve symptoms of Parkinson's disease (PD). Since there is an implication of oxidative stress in the pathophysiological mechanisms of the disease, the compounds possessing an ability to reduce the oxidative stress are prime candidates for neuroprotection. Thereby our current study is focused on the development of new multi-target PD drugs capable of inhibiting the activity of monoamine oxidase-B while exerting neuroprotective and antioxidant properties. A small series of benzimidazole derivatives containing hydroxy and methoxy arylhydrazone fragments has been synthesized and the neurotoxicity of the compounds has been evaluated in vitro on neuroblastoma SH-SY5Y cells and on isolated rat brain synaptosomes by measuring the cell viability and the levels of reduced glutathione and a good safety profile has been shown. The 2-hydroxy-4-methoxy substituted arylhydrazone 7 was the least toxic on neuronal SH-SY5Y cells and showed the lowest neurotoxicity in rat brain synaptosomes. The neuroprotective properties of the test compounds were further assessed using two models: H2O2-induced oxidative stress on SH-SY5Y cells and 6-hydroxydopamine-induced neurotoxicity in rat brain synaptosomes. Compound 7 showed more pronounced neuroprotective activity on SH-SY5Y cells, compared to the referent melatonin and rasagiline. It also preserved the synaptosomal viability and the reduced glutathione levels; the effects were stronger than those of rasagiline and comparable to melatonin. All the tested compounds were capable to inhibit human monoamine oxidase-B enzyme to a significant extent, however, compound 7 exerted the most prominent inhibitory activity, similar to selegiline and rasagiline. The carried out molecular docking studies revealed that the activity is related to the appropriate molecular structure enabling the ligand to enter deeper in the narrow and highly lipophylic active site pocket of the human monoamine oxidase-B and has a favoring interaction with the key amino acid residues Tyr326 and Cys172. Since much scientific evidence points out the implication of iron dyshomeostasis in PD, the compounds were tested to reduce the ferrous iron induced oxidative molecular damage on biologically important molecules in an in vitro lecithin containing model system. All the investigated compounds denoted protection effect, stronger than the one of the referent melatonin. In order to support the assignments of the significant neuroprotective and antioxidant pharmacological activities, the radical-scavenging mechanisms of the most promising compound 7 were evaluated using DFT methods. It was found that the most probable free radicals scavenging mechanism in nonpolar phase is the hydrogen atom transfer from the amide group of compound 7, while in polar medium the process is expected to occur by a proton transfer. The current study outlines a perspective leading structure, bearing the potential for a new anti-PD drug. All performed procedures were approved by the Institutional Animal Care Committee of the Medical University of Sofia (Bulgarian Agency for Food Safety with Permission № 190, approved on February 6, 2020).

Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B.

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1–3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4–6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC50 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.

Selected 1,3-Benzodioxine-Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors.

Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8 and CD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC50 value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC50 value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC50 values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the Ki values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate that CD8 is a potent non-selective MAO inhibitor, and CD10 is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.

Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.

Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.

Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors.

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.

Developing a Multi-target Model to Predict the Activity of Monoamine Oxidase A and B Drugs.

Monoamine oxidase inhibitors (MAOIs) are compounds largely used in the treatment of Parkinson's disease (PD), Alzheimer's disease and other neuropsychiatric disorders since they are closely related to the MAO enzymes activity. The two isoforms of the MAO enzymes, MAO-A and MAO-B, are responsible for the degradation of monoamine neurotransmitters and due to this, relevant efforts have been devoted to finding new compounds with more selectivity and less side effects. One of the most used approaches is based on the use of computational approaches since they are time and money-saving and may allow us to find a more relevant structure-activity relationship. In this manuscript, we will review the most relevant computational approaches aimed at the prediction and development of new MAO inhibitors. Subsequently, we will also introduce a new multitask model aimed at predicting MAO-A and MAO-B inhibitors. The QSAR multi-task model herein developed was based on the use of the linear discriminant analysis. This model was developed gathering 5,759 compounds from the public dataset Chembl. The molecular descriptors used was calculated using the Dragon software. Classical statistical tests were performed to check the validity and robustness of the model. The herein proposed model is able to correctly classify all the 5,759 compounds. All the statistical performed tests indicated that this model is robust and reproducible. MAOIs are compounds of large interest since they are largely used in the treatment of very serious illness. These inhibitors may lose efficacy and produce severe side effects. Due to this, the development of selective MAO-A or MAO-B inhibitors is crucial for the treatment of these diseases and their effects. The herein proposed multi-target QSAR model may be a relevant tool in the development of new and more selective MAO inhibitors.

Design, Synthesis and Evaluation of O‐Pentyne Substituted Diphenylpyrimidines as Monoamine Oxidase and Acetylcholinesterase Inhibitors

AbstractAlzheimer's disease (AD) is a multifactorial neurological disorder and single target directed drugs have been found ineffective in the retardation or reversal of disease state. In last few years, multi‐targeting agents are being explored as drug strategy for the effective treatment of AD. A series of (4‐(pent‐4‐yn‐1‐yloxy)phenyl)‐2‐phenylpyrimidine derivatives has been synthesized and evaluated against monoamine oxidase (MAO) and acetylcholinesterase (AChE) enzymes. Most of the synthesized compounds were found to be potent inhibitors of MAO−A, MAO−B and AChE enzymes with IC50 values in low micromolar range. In the series, BD‐13 and BD‐14 were found to be the most potent dual inhibitors of MAO−A and AChE enzymes. BD‐13 showed MAO−A and AChE inhibition with IC50 values of 0.78±0.12 μM and 2.84±0.19 μM, respectively. Similarly, BD‐14 showed potent inhibition activities against MAO−A and AChE enzymes with IC50 values of 0.75±0.04 μM and 2.19±0.06 μM, respectively. In reversibility studies, BD‐13 and BD‐14 were found to be reversible inhibitors of both MAO−A and AChE enzymes. In the cytotoxicity studies, BD‐13 and BD‐14 were found to be non‐toxic to the SH‐SY5Y cells. In the molecular dynamic simulation studies of 30 ns, both the potent compounds were found to be thermodynamically stable in the active sites of MAO−A and AChE. Thus, BD‐13 and BD‐14 can be used as lead compounds for the development of more potent compounds for the effective treatment of Alzheimer's disease.

Diphenylene Iodonium Is a Noncovalent MAO Inhibitor: A Biochemical and Structural Analysis.

Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin- and heme-dependent enzymes, and is often used as an NADPH oxidase inhibitor. We probed the efficacy of DPI on two well-known drug targets, the human monoamine oxidases MAO A and B. UV-visible spectrophotometry and steady-state kinetics experiments demonstrate that DPI acts as a competitive and reversible MAO inhibitor with Ki values of 1.7 and 0.3 μM for MAO A and MAO B, respectively. Elucidation of the crystal structure of human MAO B bound to the inhibitor revealed that DPI binds deeply in the active-site cavity to establish multiple hydrophobic interactions with the surrounding side chains and the flavin. These data prove that DPI is a genuine MAO inhibitor and that the inhibition mechanism does not involve a reaction with the reduced flavin. This binding and inhibitory activity against the MAOs, two major reactive oxygen species (ROS)-producing enzymes, will have to be carefully considered when interpreting experiments that rely on DPI for target validation and chemical biology studies on ROS functions.

The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells.

Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (IC50s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC50s ~9.4 μM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (Kis ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions—between the KKR molecule and MAO-A amino acid residues—to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups—such as chlorine and hydroxyl groups—are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs.

127 Successful Treatment of Major Depressive Disorder with Moclobemide After Recurrent Hyponatremia Induced by Multiple Antidepressant Classes

Antidepressant-induced hyponatremia/syndrome of inappropriate antidiuretic hormone (SIADH) can cause significant morbidity and mortality. Antidiuretic hormone release due to stimulation of central serotonin 5HT1C, 5HT2 and α-1 adrenergic receptors is thought to cause this adverse effect (Spigset, 1995). Evidence on which antidepressants are more likely to cause hyponatremia is inconsistent (Coupland, 2011; Leth-Moller, 2016). Owing to its uncommon use, there is limited and conflicting data on the risk of hyponatremia with Moclobemide, a reversible inhibitor of monoamine oxidase A (Mercier, 1997; Mazhar, 2019). There are few reports of hyponatremia induced by multiple antidepressant classes in the same patient. To add to the literature on risk of hyponatremia with Moclobemide and other antidepressants. We report a case of hyponatremia sequentially induced by multiple different antidepressant classes who was treated with Moclobemide with no recurrence of hyponatremia. We review existing literature on antidepressant-induced hyponatremia. A 67-year-old man with a history of hypertension, dyslipidemia and gout was first diagnosed with major depressive disorder at age 50 after presenting with pervasive depressed mood, anhedonia, insomnia, poor concentration and feelings of worthlessness. Investigations found no medical causes of depression. His depression remitted on Venlafaxine 75mg/day with no hyponatremia induced. During a second depressive episode 4 years later, his serum sodium (Na) dropped from a normal baseline to 122mmol/L after Venlafaxine was restarted. He appeared euvolemic on physical examination. Investigations found no other causes of hyponatremia and were consistent with SIADH, which was attributed to Venlafaxine. His depression later remitted on Mirtazapine 30mg/day with no hyponatremia induced. During his third depressive episode at age 67, he developed hyponatremia (serum Na 123mmol/L) a week after restarting Mirtazapine. His clinical picture was consistent with SIADH. He later developed hyponatremia after initiating the following antidepressants sequentially: Fluvoxamine, Agomelatine, Nortriptyline, Bupropion. Hyponatremia resolved with fluid restriction and cessation of the implicated antidepressant each time before the next was initiated. He eventually tolerated Moclobemide 300mg/day with no recurrence of hyponatremia. Agomelatine, Nortriptyline and Bupropion are reported to have a low risk of hyponatremia but were implicated in this case. Venlafaxine and Mirtazapine did not cause hyponatremia when first taken but were implicated when restarted after a period of cessation, underscoring the idiosyncratic nature of antidepressant-induced hyponatremia. Moclobemide can be considered for depressed patients with recurrent antidepressant-induced hyponatremia. Serum Na should be regularly monitored in patients taking antidepressants who are at high risk of hyponatremia.

Promising selective MAO-B inhibition by sesamin, a lignan from Zanthoxylum flavum stems

Monoamine oxidase inhibition is an important therapeutic approach for various neurodegenerative disorders. Reversible MAO inhibitors selectively targeting only one isoform possess substantial merit in terms of safety, efficacy, and side effect profile. This study aimed to isolate the secondary metabolites of Zanthoxylum flavum stems and evaluate their recombinant human MAO inhibition, antimicrobial, and antiprotozoal activities. As a result, fourteen compounds were isolated and identified (nine of them were reported from Z. flavum for the first time). Compound 3 (sesamin) exhibited potent selective MAO-B inhibition (IC50 value of 1.45 ± 0.05 µM) which reported herein for the first time. Compound 2 showed selective MAO-A inhibition activity, compound 5 exhibited good trypanocidal activity, and compound 7 displayed moderate antibacterial activity. The promising MAO-B inhibitory activity of sesamin provoked us to further explore the kinetic properties, the binding mode, and the underlying mechanism of MAO-B inhibition by this lignan. This detailed investigation substantiated a reversible binding and mixed MAO-B catalytic function inhibition via sesamin (Ki: 0.473 ± 0.076 μM). Selectivity and reversibility of sesamin on MAO-B provide exciting prerequisites for further in vivo investigation to confirm its therapeutic potentiality.

Amphetamine Derivatives as Monoamine Oxidase Inhibitors.

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.

Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B.

The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV–vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.

Effect of serotonin modulation on dystrophin-deficient zebrafish.

ABSTRACTDuchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutation of the dystrophin gene. Pharmacological therapies that function independently of dystrophin and complement strategies aimed at dystrophin restoration could significantly improve patient outcomes. Previous observations have suggested that serotonin pathway modulation ameliorates dystrophic pathology, and re-application of serotonin modulators already used clinically would potentially hasten availability to DMD patients. In our study, we used dystrophin-deficient sapje and sapje-like zebrafish models of DMD for rapid and easy screening of several classes of serotonin pathway modulators as potential therapeutics. None of the candidate drugs tested significantly decreased the percentage of zebrafish exhibiting the dystrophic muscle phenotype in the short-term birefringence assay or lengthened the lifespan in the long-term survival assay. Although we did not identify an effective drug, we believe our data is of value to the DMD research community for future studies, and there is evidence that suggests serotonin modulation may still be a viable treatment strategy with further investigation. Given the widespread clinical use of selective serotonin reuptake inhibitors, tricyclic antidepressants and reversible inhibitors of monoamine oxidase, their reapplication to DMD is an attractive strategy in the field's pursuit to identify pharmacological therapies to complement dystrophin restoration strategies.

Safinamide Mesilate (Equfina® TABLETS 50 mg): preclinical and clinical pharmacodynamics, efficacy, and safety

Parkinson's disease is a neurodegenerative disorder characterized by the degenerative loss of dopaminergic neurons in the substantia nigra. Dopamine deficiency is thought to disrupt motor control of the basal ganglia and cause characteristic motor symptoms in Parkinson's disease such as bradykinesia, akinesia, and tremor. Therefore, dopamine replacement therapy is widely used in the clinical setting. Safinamide is a novel, selective, and reversible inhibitor of monoamine oxidase B expected to increase dopamine levels in the brain and improve the symptoms of Parkinson's disease. In addition, safinamide shows non-dopaminergic actions such as sodium channel blockade and inhibition of glutamate release. Preclinical studies have demonstrated that safinamide ameliorates "wearing off" symptoms after administration in rat and monkey models with selectively destroyed dopaminergic neurons. In the monkeys, safinamide concurrently inhibited levodopa-induced dyskinesia. These findings suggest that safinamide not only increases the dopaminergic effect of levodopa, but also reduces levodopa-induced adverse events via its non-dopaminergic effects. In clinical trials of patients with Parkinson's disease with the "wearing off" phenomenon, safinamide has been found to prolong the "on time" and improve motor function as assessed by Unified Parkinson's Disease Rating Scale Part III. In Japan, safinamide was approved in September 2019 as a levodopa combination drug for Parkinson's disease with "wearing off" phenomenon. Safinamide is therefore expected to be a new treatment option for patients with Parkinson's disease.

Evaluation of Antidepressant Activity of Plocama pendula root extract

Plocama is a flowering plant genus belonging to Rubiaceae family. The natural products are soxlated from the dried powder of Plocama root with various solvents like n-Hexane, Ethyl acetate, Chloroform, Water and Ethanol. Phytochemical screening revealed that Alkaloids are present in chloroform extract whereas Anthocyanins are present in ethanol extract. Terpenoids, Flavonoids, Alkaloids and Phenolic compounds are present in water extract. In the present study, Plocama pendula root water extract (PPRWE) (400 mg/kg) produced significant antidepressant effect in Forced swim test & Tail Suspension Test. Ecliptin alkaloid & Culumbin, a flavonoid present in PPRWE may be facilitating monoaminergic transmission there by producing antidepressant effects. In this work, it was demonstrated that the administration of different doses of the water extract of Plocama pendula root in mice was able to induce antidepressant effects. On the basis of the clinical association of depressive episodes and stressful life events, many of the animal models for the evaluation of antidepressant drug activity assess stress‐precipitated behaviors. Results of this study showed that the administration of the PPRWE produced a diminution of immobility time of mice exposed to the both forced swimming and tail suspension tests. Harmaline alkaloidspresent in Plocama pendulaact as reversible monoamine oxidase inhibitors and in common with other beta carboline binds to 5‐Hydroxy Tryptamine receptors. Inhibition of this enzyme causes a reduction in metabolism and subsequent increase in the concentration of biogenic amines. The flavonoid components of PPRWE might be interacting with adrenergic and serotonergic systems in mediating the antidepressant effects of PPRWE. However, the precise mechanisms by which the extract produced antidepressant‐like effect are not completely understood. Further studies would be necessary to evaluate the contribution of active chemical constituents for the observed antidepressant activity.

Monoamine Oxidase Inhibitors: From Classic to New Clinical Approaches.

Monoamine oxidases (MAOs) are involved in the oxidative deamination of different amines and neurotransmitters. This pointed them as potential targets for several disorders and along the last 70 years a wide variety of MAO inhibitors have been developed as successful drugs for the treatment of complex diseases, being the first drugs approved for depression in the late 1950s. The discovery of two MAO isozymes (MAO-A and B) with different substrate selectivity and tissue expression patterns led to novel therapeutic approaches and to the development of new classes of inhibitors, such as selective irreversible and reversible MAO-B inhibitors and reversible MAO-A inhibitors. Significantly, MAO-B inhibitors constitute a widely studied group of compounds, some of them approved for the treatment of Parkinson's disease. Further applications are under development for the treatment of Alzheimer's disease, amyotrophic lateral sclerosis, and cardiovascular diseases, among others. This review summarizes the most important aspects regarding the development and clinical use of MAO inhibitors, going through mechanistic and structural details, new indications, and future perspectives. Monoamine oxidases (MAOs) catalyze the oxidative deamination of different amines and neurotransmitters. The two different isozymes, MAO-A and MAO-B, are located at the outer mitochondrial membrane in different tissues. The enzymatic reaction involves formation of the corresponding aldehyde and releasing hydrogen peroxide (H2O2) and ammonia or a substituted amine depending on the substrate. MAO's role in neurotransmitter metabolism made them targets for major depression and Parkinson's disease, among other neurodegenerative diseases. Currently, these compounds are being studied for other diseases such as cardiovascular ones.