MAO-B Inhibitor Research Articles

Efficacy and Safety of MAO-B Inhibitors Safinamide and Zonisamide in Parkinson's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

In Parkinson's disease, safinamide and zonisamide are novel monoamine oxidase-B inhibitors with a dual mechanism of action involving the inhibition of sodium and calcium channels and the subsequent release of glutamate. The aim of this systematic review and meta-analysis was to examine the efficacy and safety of both drugs compared with placebo on motor symptoms, cognitive function, and quality of life in patients with Parkinson's disease. We searched MEDLINE, EMBASE, Cochrane Central, Scopus, PsycINFO, and trials registries up to March 2023 for randomized controlled trials of adults with Parkinson's disease administered either safinamide or zonisamide and published in English. We excluded single-arm trials or if neither the efficacy nor safety outcomes of interest were reported. Primary outcomes were the change from baseline in Unified Parkinson's Disease Rating Scale section III (UPDRS-III) and serious adverse events. Secondary outcomes included a change from baseline in OFF-time, Parkinson's Disease Questionnaire 39 to evaluate quality of life, and Mini-Mental State Examination for cognitive function assessment. The meta-analysis was conducted using Review Manager 5.4.1. Random-effect models were used to calculate the pooled mean differences (MDs) and risk ratios with 95% confidence intervals (CIs). Subgroup analyses by medication, doses, Parkinson's disease stage, and risk of bias were conducted. We assessed the risk of bias using the Cochrane's risk of bias tool. Sensitivity analysis was conducted, and publication bias were evaluated. This meta-analysis was not externally funded, and the protocol is available on the Open Science Framework Registration ( https://doi.org/10.17605/OSF.IO/AMNP5 ). Of 3570 screened citations, 16 trials met inclusion criteria (4314 patients with Parkinson's disease). Ten safinamide trials were conducted in several countries. Six zonisamide trials were included, five of which were conducted in Japan and one in India. UPDRS Part III scores were significantly lower with both monoamine oxidase-B inhibitors than with placebo (MD = - 2.18; 95% CI - 2.88 to - 1.49; I 2 =63%; n = 14 studies). A subgroup analysis showed a significant improvement in UPDRS-III in safinamide (MD = - 2.10; 95% CI - 3.09 to - 1.11; I2 = 71%; n = 8 studies) and zonisamide (MD = - 2.31; 95% CI - 3.35 to - 1.27; I2 = 52%; n = 6 studies) compared with placebo. Monoamine oxidase-B inhibitors significantly decreased OFF-time compared with placebo. No significant differences in cognitive function (Mini-Mental State Examination), whereas an improvement in quality of life (Parkinson's Disease Questionnaire 39 scores) was observed. There was no significant difference in incidence rates of serious adverse events among all examined doses of zonisamide and safinamide compared with placebo. Two trials were reported as a high risk of bias and sensitivity analyses confirmed the primary analysis results. Evidence suggests that novel monoamine oxidase-B inhibitors not only improve motor symptoms but also enhance patients' quality of life. The meta-analysis showed that both medications have a similar safety profile to placebo with regard to serious adverse events. The overall findings emphasize the effectiveness of safinamide and zonisamide in the treatment of Parkinson's disease as adjunct therapy. Further long-term studies examining the impact of these medications on motor and non-motor symptoms are necessary.

Selegiline Modulates Lipid Metabolism by Activating AMPK Pathways of Epididymal White Adipose Tissues in HFD-Fed Obese Mice.

Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer, is among the most serious health problems. Increased monoamine oxidase (MAO) activity has been observed in the adipose tissue of obese humans and animals. Although previous studies have already demonstrated the potential of MAO-B inhibitors as a treatment for this condition, the mechanism of their effect has been insufficiently elucidated. In this study, we investigated the anti-obesity effect of selegiline, a selective MAO-B inhibitor, using in vivo animal models. The effect was evaluated through an assessment of body energy homeostasis, glucose tolerance tests, and biochemical analysis. Pharmacological inhibition of MAO-B by selegiline was observed to reduce body weight and fat accumulation, and improved glucose metabolism without a corresponding change in food intake, in HFD-fed obese mice. We also observed that both the expression of adipogenenic markers, including C/EBPα and FABP4, and lipogenic markers such as pACC were significantly reduced in epididymal white adipose tissues (eWATs). Conversely, increased expression of lipolytic markers such as ATGL and pHSL and AMPK phosphorylation were noted. Treating obese mice with selegiline significantly increased expression levels of UCP1 and promoted eWAT browning, indicating increased energy expenditure. These results suggest that selegiline, by inhibiting MAO-B activity, is a potential anti-obesity treatment.

Novel coumarin benzamides as potent and reversible monoamine oxidase-B inhibitors: Design, synthesis, and neuroprotective effects

A series of new 6-amidocoumarin derivatives, 3a–j, was synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase. All compounds, except 3 g, showed higher inhibitory activity towards MAO-B than MAO-A. Compound 3i most potently inhibited MAO-B with an IC50 value of 0.095 μM, followed by 3j (0.150 μM), 3b (0.190 μM), and 3c (0.204 μM). Compound 3i demonstrated the highest selectivity index (>421.05) for MAO-B. The remarkable MAO-B inhibitory activity of compounds 3i, 3j, 3b, and 3c highlighted the substantial role of the substituents at the 3,4-position of the terminal phenyl group in achieving optimal MAO-B inhibition, especially 3-Cl (3i) > 3-CF3 (3b). In the kinetic study, the Ki value of 3i for MAO-B was 0.046 ± 0.010 μM with a competitive reversible mode. Moreover, compounds 3i and 3j were nontoxic to normal (MDCK), cancer (HL-60), and neuroblastoma (SH-SY5Y) cells and showed protective effects against damage induced by reactive oxygen species in SH-SY5Y neuroblastoma cells. Moreover, molecular docking and molecular dynamics simulations highlighted the tight interactions of 3i with Tyr398 at the binding site of MAO-B. These findings suggest that 3i is a potent, reversible, and selective MAO-B inhibitor that could potentially treat neurological disorders.

MAO-B Inhibitor (2E)-3-(4-Bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one as a Neuroprotective Agent Against Alzheimer's Disease.

Chalcones (trans-1,3-diphenyl-2-propen-1-ones) form simple chemical structures that act as precursors for the biogenesis of flavonoids. These are distributed in plants and have two aromatic or heteroaromatic rings connected by a three-carbon α, β-unsaturated carbonyl group. Considering the importance of chalcones as monoamine oxidase and acetylcholinesterase inhibitors, the study was designed as a comprehensive and systematic analysis to evaluate the pharmacological activities leading to the formation of drug molecules against Alzheimer's disease (AD). Based on our previous research, 11 indolyl chalcones (IC1-IC11) were synthesised and investigated for MAO-B inhibitory activity. The inhibitory potential was evaluated based on binding and reversibility studies using purified enzymes. The active and most promising molecule, (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9), also found predominant acetylcholinesterase inhibition and hence it was found dual acting in vitro. Based on this, the molecule IC9 was further subjected to cell line studies to further explore its role as a neuroprotective agent against neuronal degeneration, one of the main contributing parameters related to AD.

Inhibitions of monoamine oxidases by ferulic acid hydrazide derivatives: synthesis, biochemistry, and computational evaluation

Monoamine oxidases (MAOs) regulate neurotransmitters, and changes in their regulation lead to neurogenerative diseases (NDs). Therefore, MAO inhibitors are used to treat NDs. Ferulic acid, a phenolic compound found in various plant species, has been demonstrated to have a variety of biological functions, including anti-inflammatory, anticancer, and neuroprotective effects. In this study, ten ferulic acid hydrazide derivatives (FA1–FA10) were synthesized, and their ability to inhibit monoamine oxidase (MAO) enzymes was tested. Six candidates demonstrated a more pronounced pattern of inhibitory action against MAO-B than against MAO-A. FA3 had the highest inhibitory efficacy in MAO-B inhibition (IC50 value of 1.88 μM), followed by FA9 (2.08 μM). FA3 has a Ki of 1.92 ± 0.73 μM. A reversibility experiment of MAO-B inhibition by FA3 was conducted using dialysis, and the recovery pattern showed FA3 was a reversible MAO-B inhibitor with a similar recovery to safinamide, a reversible reference inhibitor. These results indicate that FA3 is an effective reversible MAO-B inhibitor. In molecular dynamics and docking, FA3 paired with pi-pi stacking helped stabilize the protein ligand in the active site of MAO-B. According to this study, lead compounds can be used as therapeutic agents to treat neurological conditions, such as Parkinson's disease (PD).

Recent advances on the role of monoamine oxidases in cardiac pathophysiology

Numerous physiological and pathological roles have been attributed to the formation of mitochondrial reactive oxygen species (ROS). However, the individual contribution of different mitochondrial processes independently of bioenergetics remains elusive and clinical treatments unavailable. A notable exception to this complexity is found in the case of monoamine oxidases (MAOs). Unlike other ROS-producing enzymes, especially within mitochondria, MAOs possess a distinct combination of defined molecular structure, substrate specificity, and clinically accessible inhibitors. Another significant aspect of MAO activity is the simultaneous generation of hydrogen peroxide alongside highly reactive aldehydes and ammonia. These three products synergistically impair mitochondrial function at various levels, ultimately jeopardizing cellular metabolic integrity and viability. This pathological condition arises from exacerbated MAO activity, observed in many cardiovascular diseases, thus justifying the exploration of MAO inhibitors as effective cardioprotective strategy. In this context, we not only summarize the deleterious roles of MAOs in cardiac pathologies and the positive effects resulting from genetic or pharmacological MAO inhibition, but also discuss recent findings that expand our understanding on the role of MAO in gene expression and cardiac development.

Impact of Safinamide on Patient-Reported Outcomes in Parkinson's Disease.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative condition due to the degeneration of nigral dopaminergic cells. Both motor and non-motor symptoms (NMS) of PD produce a marked impairment in PD patients' quality of life (QoL), but contrary to motor features, NMS do not improve with dopamine replacement. Novel therapeutic interventions for PD have successfully controlled most motor manifestations of PD, but the management of NMS is still challenging. Since NMS have a negative impact on the QoL of PD patients, researchers are currently looking for drugs that can modulate the activity of neurotransmitter systems other than dopamine in the hope that can alleviate NMS in PD. Among the recently approved drugs for patients experiencing fluctuations in motor symptoms, safinamide stands out as an effective add-on therapy to levodopa. Safinamide is a monoamine oxidase type-B inhibitor (MAOB-I), with proven efficacy in reducing motor fluctuations. Its distinctive mechanism of action impacts dopaminergic pathways via MAOB inhibition and glutamatergic pathways by blocking sodium and calcium channels. Findings from Phase III clinical trials, meta-analysis, post-hoc analysis, and real-life experiences indicate that safinamide benefits motor symptoms such as tremor, bradykinesia, rigidity, and gait. Additionally, it shows promise for improving NMS like fatigue, pain, mood, and sleep disturbances in patients with PD. In this article, the authors explore the impact of safinamide on patient-reported outcomes in PD. A thorough search was conducted on PubMed focusing on studies published between 2018 and 2023 in English. The inclusion criteria encompassed clinical trials, randomized controlled trials, systematic reviews, meta-analyses, and reviews. The search strategy revolved around the implementation of MeSH terms related to safinamide and its impact on the quality of life in PD. Our data strongly support the improving effect on QoL, reducing the disabling NMS reported in patients with PD.

The Effect of Selegiline on Reducing Oxidative Stress in Polymorphonuclear Blood Cells (Lymphocytes) Isolated from Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a persistent condition resulting in an inflammatory response abide by the pathological mechanism of autoimmunity that causes the cartilage, bone, and joint tissues to deteriorate, lowering one’s quality of life in general. Several studies have suggested a significant association between oxidative stress caused by leukocyte-mediated inflammatory responses and the conversion of a substantial amount of oxygen into diverse free radicals, resulting in oxidative harm, including the chronic nature of rheumatoid arthritis. The utilization of DMARDs which are known as biologic and conventional disease-modifying antirheumatic drugs, has exhibited encouraging results. However, it is crucial to prioritize the discovery of novel and efficacious medications for rheumatoid arthritis in order to address the constraints associated with current therapeutic approaches. Selegiline, a synthetic drug primarily employed to manage Parkinson’s disease, predominantly interferes with the MAO-B enzyme, also known as monoamine oxidase. Additionally, it has been demonstrated to possess free radical-neutralizing properties. The goal of this study is to assess the effectiveness of selegiline in reducing oxidative stress indicators in peripheral blood mononuclear lymphocyte cells isolated from individuals diagnosed with RA. Peripheral blood was collected from 20 RA patients in accordance with the American College of Rheumatology standard. Lymphocytes were isolated following incubation with 1.5 μg/mL phorbol myristate acetate (PMA) and treatment with different concentrations (50–200 μg/mL) of selegiline. This study reveals that selegiline in concentrations of 150 and 200 μg/mL was effective enough to alleviate oxidative stress by scavenging free radicals and improving the level of natural defensive enzymes playing as antioxidants. Therefore, it can be concluded that the MAO-B inhibitor selegiline has potential as a non-toxic repurposed medicine for curtailing the pathological effects of oxidative overload during RA, unlocking the opportunity for further investigation into the impact on other inflammatory cells, such as neutrophils.

2-Oxoquinoline-based-thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors.

Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long-term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2-oxoquinoline-based thiosemicarbazones 9a-r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO-A and MAO-B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO-A, MAO-B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 μM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023.

Monoamine oxidases (MAOs) are a family of flavin adenine dinucleotide-dependent enzymes that catalyze the oxidative deamination of a wide range of endogenous and exogenous amines. Multiple neurological conditions, including Parkinson's disease (PD) and Alzheimer's disease (AD), are closely correlated with altered biogenic amine concentrations in the brain caused by MAO. Toxic byproducts of this oxidative breakdown, including hydrogen peroxide, reactive oxygen species, and ammonia, can cause oxidative damage and mitochondrial dysfunction in brain cells. Certain MAO-B blockers have been recognized as effective treatment options for managing neurological conditions, including AD and PD. There is still a pressing need to find potent therapeutic molecules to fight these disorders. However, the focus of neurodegeneration studies has recently increased, and certain compounds are now in clinical trials. Chromones are promising structures for developing therapeutic compounds, especially in neuronal degeneration. This review focuses on the MAO-B inhibitory potential of several synthesized chromones and their structural activity relationships. Concerning the discovery of a novel class of effective chromone-based selective MAO-B-inhibiting agents, this review offers readers a better understanding of the most recent additions to the literature.

Pharmacological and toxicological evaluation of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxoide against haloperidol induced Parkinson like symptoms in animal model: In-vitro and in-vivo studies

In Parkinson's disease (PD), degradation of dopaminergic neurons in substantia nigra causes striatal deficiency of dopamine, which results in tremors, bradykinesia with instability in posture, rigidity and shuffled gait. Prevalence of PD increases with age as from 65 to 85 years. In an attempt to devise targeted safe therapy, nanoparticles of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (MBD) (MBDN), were prepared and their acute toxicity and safety was evaluated. Thirty-six healthy albino mice were randomly divided into six groups (n = 6): normal control, diseased control, standard (levodopa/carbidopa (100/25 mg/kg) and the remaining three groups were administered 1.25, 2.5 and 5 mg/kg MBDN during 21 days study. Except control, all mice, were injected haloperidol (1 mg/ kg i.p.) 1-h prior to treatment to induce PD. Acute toxicity test showed, no effect of MBDN on lipid profile, brain, renal and liver function and histoarchitecture of kidney, liver and heart, except decreased (p < 0.05) platelet count. Behavioral studies showed significant improvement (p < 0.001) in motor function and reduction of oxidation status in a MBDN in a dose dependent manner. Thus, the study findings revealed significance of MBDN as a selective MAO-B inhibitor for the improvement of Parkinson's symptoms in animal model.

Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA.

The lateral hypothalamic area (LHA) regulates food intake and energy balance. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we show that GABRA5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity mouse models in males. Chemogenetic inhibition of GABRA5LHA suppresses fat thermogenesis and increases weight gain, whereas gene silencing of GABRA5 in LHA decreases weight gain. In the diet-induced obesity mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by monoamine oxidase B (Maob). Gene silencing of astrocytic Maob in LHA facilitates fat thermogenesis and reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a Maob inhibitor, KDS2010. We propose that firing of GABRA5LHA suppresses fat accumulation and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

In Vitro Evaluation of the Potential for Drug Interactions by Salidroside.

Several studies utilizing Rhodiola rosea, which contains a complex mixture of phytochemicals, reported some positive drug-drug interaction (DDI) findings based on in vitro CYP450's enzyme inhibition, MAO-A and MAO-B inhibition, and preclinical pharmacokinetic studies in either rats or rabbits. However, variation in and multiplicity of constituents present in Rhodiola products is a cause for concern for accurately evaluating drug-drug interaction (DDI) risk. In this report, we examined the effects of bioengineered, nature-identical salidroside on the inhibition potential of salidroside on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 utilizing human liver microsomes, the induction potential of salidroside on CYP1A2, CYP2B6 and CYP3A4 in cryopreserved human hepatocytes, the inhibitory potential of salidroside against recombinant human MAO-A and MAO-B, and the OATP human uptake transport inhibitory potential of salidroside using transfected HEK293-OATP1B1 and OATP1B3 cells. The results demonstrate that the bioengineered salidroside at a concentration exceeding the predicted plasma concentrations of <2 µM (based on 60 mg PO) shows no risk for drug-drug interaction due to CYP450, MAO enzymes, or OATP drug transport proteins. Our current studies further support the safe use of salidroside in combination with other drugs cleared by CYP or MAO metabolism or OATP-mediated disposition.

Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease.

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 μM, followed by IHC2 (IC50 = 16.934 μM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

Integrated structure model-based virtual screening approaches identified anti-cancer agents against prostate cancer by targeting MAOB protein

BackgroundFlavin monoamine oxidase gene encodes a protein (MAOB) that forms a part of the flavin monoamine oxidase family in the outer membrane of mitochondria. It plays a role in the tissue metabolism of neuroactive and vasoactive amines as well as the oxidative deamination of xenobiotic and biogenic amines. However, overexpression of the receptor reduced apoptosis in cells, resulting in the progress of prostate sarcoma. Therefore, various kinds of MAOB antagonists are often used to fix an apoptosis mechanism that makes it hard to get rid of cancer from live tissues. Moreover, chemical compounds that have been discovered to be MAOB inhibitors to date exhibit side effects that are causing problems in chemotherapy treatment. The study aims to discover new purchasable compound that induces apoptosis by allowing caspases to operate at their maximum efficiency and is low toxic.MethodsWith the assistance of virtual screening, molecular docking, and molecular dynamics simulation (MD), a structure-based pharmacophore model of the protein active site cavity was made. Twenty hits were found, and then a molecular docking strategy was used to choose four molecules to study in more depth. MD simulations were used to check the stability of the four compounds, and they were all shown to be stable when bound to the target protein.ResultsFour newly discovered compounds, included with ZINC ID Such as ZINC12143050, ZINC08301324, ZINC16743012, and ZINC64165826 with binding scores of − 11.7, − 11.4, − 11.2 and − 11.1 kcal/mol, respectively, may serve as lead compounds for the treatment of prostate cancer associated with MAOB; however, further evaluation through wet lab is needed to determine the compounds effectiveness.ConclusionA structure-based model was initially developed, followed by molecular docking, ADMET analysis, and MD simulation. The top four natural compounds identified in the A-to-Z virtual screening process could serve as lead molecules in the fight against prostate cancer.

The evaluation of isatin analogues as inhibitors of monoamine oxidase.

The small molecule, isatin, is a well-known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC50 values of 12.3 and 4.86 μM for MAO-A and MAO-B, respectively. While the interaction of isatin with MAO-B has been characterized, only a few studies have explored structure-activity relationships (SARs) of MAO inhibition by isatin analogues. The current study therefore evaluated a series of 14 isatin analogues as in vitro inhibitors of human MAO-A and MAO-B. The results indicated good potency MAO inhibition for some isatin analogues with five compounds exhibiting IC50 < 1 μM. 4-Chloroisatin (1b) and 5-bromoisatin (1f) were the most potent inhibitors with IC50 values of 0.812 and 0.125 μM for MAO-A and MAO-B, respectively. These compounds were also found to be competitive inhibitors of MAO-A and MAO-B with Ki values of 0.311 and 0.033 μM, respectively. Among the SARs, it was interesting to note that C5-substitution was particularly beneficial for MAO-B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated.

Synthesis and anti-cancer potential of potent peripheral MAOA inhibitors designed to limit blood:brain penetration

Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi’s) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.

Dose- and application route-dependent effects of betahistine on behavioral recovery and neuroplasticity after acute unilateral labyrinthectomy in rats.

Betahistine is widely used for the treatment of various vestibular disorders. However, the approved oral administration route and maximum daily dose are evidently not effective in clinical trials, possibly due to a major first-pass metabolism by monoamine oxidases (MAOs). The current study aimed to test different application routes (i.v./s.c./p.o.), doses, and concurrent medication (with the MAO-B inhibitor selegiline) for their effects on behavioral recovery and cerebral target engagement following unilateral labyrinthectomy (UL) in rats. Sixty rats were subjected to UL by transtympanic injection of bupivacaine/arsanilic acid and assigned to five treatment groups: i.v. low-dose betahistine (1 mg/kg bid), i.v. high-dose betahistine (10 mg/kg bid), p.o. betahistine (1 mg/kg bid)/selegiline (1 mg/kg once daily), s.c. betahistine (continuous release of 4.8 mg/day), and i.v. normal saline bid (sham treatment; days 1-3 post-UL), respectively. Behavioral testing of postural asymmetry, nystagmus, and mobility in an open field was performed seven times until day 30 post-UL and paralleled by sequential cerebral [18F]-FDG-μPET measurements. The therapeutic effects of betahistine after UL differed in extent and time course and were dependent on the dose, application route, and selegiline co-medication: Postural asymmetry was significantly reduced on 2-3 days post-UL by i.v. high-dose and s.c. betahistine only. No changes were observed in the intensity of nystagmus across groups. When compared to sham treatment, movement distance in the open field increased up to 5-fold from 2 to 30 days post-UL in the s.c., i.v. high-dose, and p.o. betahistine/selegiline groups. [18F]-FDG-μPET showed a dose-dependent rCGM increase in the ipsilesional vestibular nucleus until day 3 post-UL for i.v. high- vs. low-dose betahistine and sham treatment, as well as for p.o. betahistine/selegiline and s.c. betahistine vs. sham treatment. From 1 to 30 days post-UL, rCGM increased in the thalamus bilaterally for i.v. high-dose betahistine, s.c. betahistine, and p.o. betahistine/selegiline vs. saline treatment. Betahistine has the potential to augment the recovery of dynamic deficits after UL if the administration protocol is optimized toward higher effective plasma levels. This may be achieved by higher doses, inhibition of MAO-based metabolism, or a parenteral route. In vivo imaging suggests a drug-target engagement in central vestibular networks.

N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease

The oxindole core is an important structural motif in many natural and synthetic substances with various biological activities including anticancer, antineurodegenerative, and antimicrobial properties. This report focuses on the synthesis and biological activity of a series of novel N-substituted 3-aminooxindoles and their assessment in cholinesterase (ChE) and monoamine oxidase (MAO) inhibition. With regard to MAO inhibition, a series of N-propargyl containing derivatives was synthesized and screened. Despite being weak inhibitors of MAO-A and MAO-B, the compounds were selective for butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Most of them were strong inhibitors of BuChE with IC50's of less than 1 µM, and one compound showed an IC50 = 27 nM. The mechanism of action of the inhibition was pin-pointed through molecular modeling, and was validated using saturation-transfer-difference (STD) NMR. Some of the compounds were screened for anti-oxidant properties, but showed no activity. The same compounds were screened in the neurodegenerative disease model cell-line SH-SY5Y and although some were found to be non-cytotoxic, others were moderately cytotoxic. Continuous live cell imaging experiments showed that the compounds do not induce relevant cell damage and thus, the compounds might be interesting drug candidates for Alzheimer’s disease. Furthermore, the most active compounds showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME, and the pharmacokinetic simulations indicated that all these compounds cross the blood-brain-barrier.

Parkinson’s disease. Focus on early stages

The review presents current data on the peculiarities of the neurodegenerative process in the early stages of Parkinson’s disease (PD) and considers the hypothesis of the presence of body-first and brain-first subtypes of the disease onset. The earliest manifestations of the disease include symptoms such as parasomnia, constipation, hyposmia, anxiety-depressive disorder, daytime sleepiness, color perception changes, cognitive dysfunction, and mild motor manifestations. The diagnosis of PD can be made when characteristic motor manifestations occur: hypokinesia, rest tremor, muscle rigidity. Substantia nigra ultrasound, magnetic resonance imaging in SWI mode, and functional neuroimaging methods are used as confirmatory methods. The approach to the treatment of early stages of PD is age dependent. Patients over 70 years of age are recommended to start therapy with levodopa; younger patients – with dopamine receptor agonists (ADR), amantadines, MAO-B inhibitors. The mechanisms of ADR action, the possibility of their influence on the motor and non-motor symptoms of PD are analyzed. A special place is given to piribedil, which, due to the dual mechanism of action, has a positive effect on cognitive functions, depression, apathy, as well as a minimal effect on daytime sleepiness.