MAO-B Inhibitor Research Articles

Pharmacotherapy of motor symptoms in early and mid-stage Parkinson's disease: guideline "Parkinson's disease" of the German Society of Neurology.

There are multiple pharmacological treatment options for motor symptoms of Parkinson's disease (PD). These comprise multiple drug classes which are approved for the condition, including levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, NMDA-receptor antagonists, anticholinergics, and others. Some of the drugs are approved for monotherapy and combination therapy while others are only approved as adjunctive therapy to levodopa. Furthermore, treatment for special treatment situations, e.g., rescue medication for off-phases, for tremor, treatment during pregnancy and breast feeding is discussed and recommendations are given with further details. The recommendations were based on systematic literature reviews, drafted by expert teams, consented in online polls followed by online consensus meetings of the whole German Parkinson's Guideline Group, and publicly released in November 2023. In the new S2k (i.e., consensus-based) guidelines, the pharmacotherapy of the motor symptoms of PD is discussed in five chapters. These comprise "Parkinson medication", "Initial monotherapy", "Early combination therapy", "Fluctuations and dyskinesia", and "Parkinsonian tremor". Furthermore, there is a chapter for special treatment situations, including perioperative management, freezing of gait, and pregnancy and breastfeeding. The recommendations for the pharmacotherapy of motor symptoms of PD have been updated. Newly available drugs have been added, while other drugs (e.g., ergoline dopamine agonists, anticholinergics, budipine) have been removed from the recommendations.

Development, characterization and pharmacokinetic evaluation of selegiline HCl loaded cubosomal thermoreversible mucoadhesive gel for nose to brain delivery

Selegiline HCl (SGH) is MAO-B inhibitor with limited bioavailability due to extensive hepatic metabolism. Thus, this work aims to formulate and evaluate SGH loaded intranasal thermoreversible cubosomal gel in order to enhance its bioavailability and ensure efficient brain targeting. Experimental design and Artificial Neural Network (ANN) were explored to optimize the formulation. Gellan gum and konjac gum were used as gelling agent and mucoadhesive agent respectively to formulate mucoadhesive in situ nasal gel. Optimized formulation of SGH loaded cubosomal dispersion exhibits average particle size (166.8 ± 3.12 nm), entrapment efficiency (72.85 ± 1.50 %), and drug release at 6 h (89.15 ± 1.04 %). In vitro drug release analysis demonstrated the sustained release pattern. In vivo pharmacokinetic studies in Swiss Albino mice showed approximately 1.90-fold increase in Cmax and AUC(0-t) in brain after intranasal administration. The Cmax and AUC for drug solution was found to be 4.3828 ± 0.02 ng/mL, 19.4166 ± 0.06 ng min/mL and for cubosomal gel it was 11.7665 ± 0.32 ng/mL, 36.9216 ± 0.41 ng min/mL respectively. Furthermore, the stability study was executed for estimation of shelf life of optimized formulation. The shelf life of SGH loaded cubosmal gel was found to be 20.64 months which demonstrate its long-term stability. The in vitro and in vivo evaluation endorsed that the fabricated cubosomal in situ nasal gel could be the promising approach for nose to brain delivery of SGH in Parkinson's therapy.

Effect of halogens on 3-[4-(dimethylamino) phenyl]-1-phenylprop-2-en-1-ones: development of a new class of monoamine oxidase-B inhibitors

Five dimethylamino-based chalcone derivatives (AC) were synthesized and evaluated for their inhibition degree against monoamine oxidase (MAO) enzymes. All AC compounds showed better inhibitory activity against MAO-B than that against MAO-A. AC4 showed the highest inhibitory ability with an IC50 value of 0.020 µM, similar to that of a reference drug safinamide (IC50 = 0.019 µM) against MAO-B, followed by AC1 (IC50 = 0.068 µM) and AC3 (IC50 = 0.083 µM). Substituent -F in ring A (AC4) increased the MAO-B inhibition, followed by -H (AC1), -Br (AC3), and -Cl (AC2). The selectivity index (SI) value of AC4 was high (SI = 82.00) as well as other compounds (44.41 to 98.15). AC4 was found to be a reversible inhibitor as confirmed through analysis using the dialysis method. Interestingly, AC4 was observed to be a noncompetitive MAO-B inhibitor with a rare case and with Ki values of 0.011 ± 0.0036 µM. These experiments confirmed that AC4 is a reversible and potent selective inhibitor of MAO-B. Molecular docking experiments revealed that AC4 showed the highest inhibitory activity with a docking score (-9.510 kcal/mol). A study using molecular dynamics modeling revealed that the protein–ligand complex was more stable. It was observed that AC4 was non-cytotoxic in the study using L929 cell line. In conclusion, compound AC4 shows promise as a MAO-B inhibitor.

Inhibition of monoamine oxidases and neuroprotective effects: chalcones vs. chromones.

Eighteen compounds derived from two sub-series, (HC1-HC9) and (HF1-HF9), were synthesized and evaluated for their inhibitory activities against monoamine oxidase (MAO). HC (chalcone) series showed higher inhibitory activity against MAO-B than against MAO-A, whereas the HF (chromone) series showed reversed inhibitory activity. Compound HC4 most potently inhibited MAO-B with an IC50 value of 0.040μM, followed by HC3 (IC50 = 0.049μM), while compound HF4 most potently inhibited MAO-A (IC50 = 0.046μM), followed by HF2 (IC50 = 0.075μM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OC2H5 in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the -OC2H5 substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially -OC2H5 (HC4) > -OCH3 (HC3) > -F (HC7) > -CH3 (HC2) > -Br (HC8) > -H (HC1) in order. In MAO-A inhibition, the substituent 4-OC2H5 in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by -CH3 (HF2), -F (HF7), -Br (HF8), -OCH3 (HF3), and-H (HF1). In the enzyme kinetics and reversibility study, the Ki value of HC4 for MAO-B was 0.035 ± 0.005μM, and that of HF4 for MAO-A was 0.035 ± 0.005μM, and both were reversible competitive inhibitors. We confirmed that HC4 and HF4 significantly ameliorated rotenone-induced neurotoxicity, as evidenced by the reactive oxygen species and superoxide dismutase assays. This study also supports the significant effect of HC4 and HF4 on mitochondrial membrane potential in rotenone-induced toxicity. A lead molecule was used for molecular docking and dynamic simulation studies. These results show that HC4 is a potent selective MAO-B inhibitor and HF4 is a potent MAO-A inhibitor, suggesting that both compounds can be used as treatment agents for neurological disorders.

3D-QSAR, Pharmacophore Modeling, ADMET, and DFT Studies of Halogenated Conjugated Dienones as Potent MAO-B Inhibitors.

It has been reported that the extension of conjugation in chalcone scaffolds considerably enhanced the potency, selectivity, reversibility, and competitive mode of MAO-B inhibition. In this study, using the experimental results of IC50 values of fifteen halogenated conjugated dienone derivatives (MK1-MK15) against MAO-B, we developed a 3DQSAR model. Further, we created a 3D pharmacophore model in active compounds in the series. The built model selected three variables (G2U, RDF115m, RDF155m) among the 653 AlvaDesc molecular descriptors, with a r2 value of 0.87 and a Q2 cv for cross-validation equal to 0.82. The three variables were mostly associated with the direction of symmetry and the likelihood of discovering massive atoms at great distances. The evaluated molecules exhibited a good correlation between experimental and predicted data, indicating that the IC50 value of the structure MK2 was related to the interatomic distances of 15.5 Å between bromine and chloro substituents. Furthermore, the molecules in the series with the highest activity were those with enhanced second component symmetry directional index from the 3D representation, which included the structures MK5 and MK6. Additionally, a pharmacophore hypothesis was developed and validated using the decoy Schrodinger dataset, with an ROC score of 0.87 and an HHRR 1 fitness score that ranged from 2.783 to 3.00. The MK series exhibited a significant blood-brain barrier (BBB) permeability, according to exploratory analyses and in silico projections, and almost all analogues were expected to have strong BBB permeability. Further DFT research revealed that electrostatics were important in the interactions with MAO-B.

Interaction of dihydrofuran-2-one and its derivatives with either MAO-B or COMT enzymes using a theoretical model

There are several drugs for treating Parkinson's such as L-Dopa, carbidopa, benserazide, entacapone, bromocriptine, safinamide, rasagiline, and others. However, some of these drugs can produce some secondary effects such as hypotension, insomnia, dizziness, nausea, and constipation. In the search for a new therapeutic alternative for treating Parkinson´s, this study aimed to evaluate the theoretical interaction of Dehydrofuran-2-one (1) and their derivatives (2-31) with both MAO-B and COMT enzymes. To evaluate the interaction of Dehydrofuran-2-one (1) and their derivatives (2-31) with both MAO-B and COMT enzymes, the 1gos and 1vid proteins as theoretical tools. Besides, some drugs, such as selegiline, rasagiline, safinamide, entacapone, and tolcapone, were used as controls in the DockingServer program. The results showed differences in the interaction of compounds 1-31 with either 1gos or 1vid proteins surface compared to the controls. Other data showed that inhibition constants (Ki) for 2, 3, 12, and 26 were lower compared to selegeline, rosagiline, and sofinamide, respectively. In addition, the Ki for 1-3, 7, 9, 10, 13, 21, and 25 were lower than entacapone and tolcapone. These data suggest that 1-3, 12, and 26 could act as MAO-B inhibitors and compounds 1-3, 7, 9, 10, 13, 21, and 26 as COMT antagonists. In conclusion, these compounds may be a good therapeutic alternative for treating Parkinson´s disease.

Linalool and Geraniol Defend Neurons from Oxidative Stress, Inflammation, and Iron Accumulation in In Vitro Parkinson's Models.

Parkinson's disease is one of the most prevalent neurological disorders affecting millions of people worldwide. There is a growing demand for novel and natural substances as complementary therapies. Essential oils and their various compounds are highly investigated natural plant-based products as potential treatment options for common human diseases, such as microbial infections, chronic diseases, and neurodegenerative disorders. The present study focuses on the beneficial effects of linalool and geraniol, the major compounds of lavender (Lavandula angustifolia L.) and geranium (Pelargonium graveolens L'Hér. in Aiton) essential oils, on oxidative stress, inflammation, and iron metabolism of the rotenone and 6-hydroxydopamine-induced in vitro Parkinson's models. The experiments were carried out on all-trans retinoic acid differentiated SH-SY5Y cells. The effects of linalool and geraniol were compared to rasagiline, an MAO-B inhibitor. The results revealed that both essential oil compounds reduce the level of reactive oxygen species and alter the antioxidant capacity of the cells. They lower the secretion of IL-6, IL-8, and IL-1β pro-inflammatory cytokines. Moreover, linalool and geraniol change the expression of iron-related genes, such as the iron importer transferrin receptor 1, heme-oxygenase-1, and ferroportin iron exporter, and influence the intracellular iron contents. In addition, it has been unveiled that iron availability is concatenated with the actions of the essential oil compounds. Based on the results, linalool and geraniol are vigorous candidates as an alternative therapy for Parkinson's disease.

Synthesis and evaluation of 2-methylbenzothiazole derivatives as monoamine oxidase inhibitors

AbstractNeurodegenerative disorders are caused by the progressive death of neuronal cells in specific regions of the brain and spinal cord. The most common neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease. The inhibition of enzymes that metabolise neurotransmitter amines is an important approach in the treatment of these disorders and monoamine oxidase (MAO) B inhibitors have thus been used for the treatment of Parkinson’s disease. Inhibitors of the MAO-A isoform, in turn, are used clinically for the treatment of affective (e.g., major depression) and anxiety disorders. Recent studies have shown that benzothiazole derivatives act as potent MAO inhibitors. Based on these findings, the present study group synthesised thirteen 2-methylbenzo[d]thiazole derivatives and evaluated their in vitro MAO inhibition properties. The results showed that the benzothiazole derivatives were potent and selective inhibitors of human MAO-B, with all compounds exhibiting IC50 values < 0.017 µM. The most potent MAO-B inhibitor (4d) had an IC50 value of 0.0046 µM, while the most potent MAO-A inhibitor (5e) had an IC50 value of 0.132 µM. It may be concluded that active benzothiazole derivatives may serve as potential leads for the development of MAO inhibitors for the treatment of neuropsychiatric and neurodegenerative disorders.

Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

Ten isatin-based hydrazone derivatives were synthesized using two subseries, IA (isatin + acetophenone) and IB (isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the IB series showed more effective MAO-A inhibitory activity than IA series. Compound IB4 most potently inhibited MAO-A (half maximal inhibitory concentration IC50 = 0.015 µM), followed by IB3 (IC50 = 0.019 µM). On the contrary, compound IB3 showed the highest MAO-B inhibition (IC50 = 0.068 µM), followed by IB4 (IC50 = 1.87 µM). Compound IB3 and IB4 had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of IA series decreased the inhibition of both MAO-A and MAO-B. Among them, IB3 and IB4 (4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant Ki values of IB3 and IB4 for MAO-A were 0.0088 and 0.0063 µM, respectively, and those for MAO-B were 0.048 and 0.060 µM, respectively. IB3 and IB4 were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that IB3 and IB4 formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that IB3 and IB4 are stable with both MAO isoforms. These observations suggest IB3 and IB4 are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders.

Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.

Levodopa-induced dyskinesia in Parkinson's disease: Insights from cross-cohort prognostic analysis using machine learning

BackgroundProlonged levodopa treatment in Parkinson's disease (PD) often leads to motor complications, including levodopa-induced dyskinesia (LID). Despite continuous levodopa treatment, some patients do not develop LID symptoms, even in later stages of the disease. ObjectiveThis study explores machine learning (ML) methods using baseline clinical characteristics to predict the development of LID in PD patients over four years, across multiple cohorts. MethodsUsing interpretable ML approaches, we analyzed clinical data from three independent longitudinal PD cohorts (LuxPARK, n = 356; PPMI, n = 484; ICEBERG, n = 113) to develop cross-cohort prognostic models and identify potential predictors for the development of LID. We examined cohort-specific and shared predictive factors, assessing model performance and stability through cross-validation analyses. ResultsConsistent cross-validation results for single and multiple cohort analyses highlighted the effectiveness of the ML models and identified baseline clinical characteristics with significant predictive value for the LID prognosis in PD. Predictors positively correlated with LID include axial symptoms, freezing of gait, and rigidity in the lower extremities. Conversely, the risk of developing LID was inversely associated with the occurrence of resting tremors, higher body weight, later onset of PD, and visuospatial abilities. ConclusionsThis study presents interpretable ML models for dyskinesia prognosis with significant predictive power in cross-cohort analyses. The models may pave the way for proactive interventions against dyskinesia in PD by optimizing levodopa dosing regimens and adjunct treatments with dopamine agonists or MAO-B inhibitors, and by employing non-pharmacological interventions such as dietary adjustments affecting levodopa absorption for high-risk LID patients.

Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives.

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 μM, followed by S16 (IC50 = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 μM, followed by S5 (IC50 = 3.857 μM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.

A Review on Therapeutic Strategies against Parkinson's Disease: Current Trends and Future Perspectives.

Parkinson's Disease (PD) is the most common neurodegenerative disorder after Alzheimer's Disease and is clinically expressed by movement disorders, such as tremor, bradykinesia, and rigidity. It occurs mainly in the extrapyramidal system of the brain and is characterized by dopaminergic neuron degeneration. L-DOPA, dopaminergic agonists, anticholinergic drugs, and MAO-B inhibitors are currently used as therapeutic agents against PD, however, they have only symptomatic efficacy, mainly due to the complex pathophysiology of the disease. This review summarizes the main aspects of PD pathology, as well as, discusses the most important biochemical dysfunctions during PD, and presents novel multi-targeting compounds, which have been tested for their activity against various targets related to PD. This review selects various research articles from main databases concerning multi-targeting compounds against PD. Molecules targeting more than one biochemical pathway involved in PD, expected to be more effective than the current treatment options, are discussed. A great number of research groups have designed novel compounds following the multi-targeting drug approach. They include structures combining antioxidant, antiinflammatory, and metal-chelating properties. These compounds could be proven useful for effective multi-targeted PD treatment. Multi-targeting drugs could be a useful tool for the design of effective antiparkinson agents. Their efficacy towards various targets implicated in PD could be the key to the radical treatment of this neurodegenerative disorder.

Investigation of 3-Phenylcoumarin Derivatives as Potential Multi-target Inhibitors for Human Cholinesterases and Monoamine oxidases: A Computational Approach.

Alzheimer's disease (AD) is the predominant etiology of dementia, impacting a global population of approximately 50 million individuals. In the field of medicinal chemistry, there have been notable advancements in the utilization of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors for the purpose of addressing the neurotransmitter shortage associated with Alzheimer's disease (AD). A selection of previously synthesized 3-Phenylcoumarin derivatives (5a-m) were selected for examination in the pursuit of potential multi-targeting inhibitors of MAO-A, MAO-B, AChE, and BChE. The stability and reactivity of the compounds were investigated through the utilization of density functional theory (DFT) simulations. Subsequently, a CoMFA technique, grounded in 3D-QSAR principles, was employed to construct a model and predict the inhibitory properties of analogues belonging to the class of 3-phenylcoumarin derivatives. Through the application of molecular docking methodologies, we have employed predictive analyses to determine the potential binding interactions and stability of the drugs under investigation. The results obtained from the present investigation indicate that the 3-phenylcoumarin derivatives possess a reactive electronic characteristic that is crucial for their anti-cholinesterase activity. Compound 5a demonstrated a noteworthy binding score with AChE, BChE, MAO-A and MAO-B, respectively, indicating a robust binding affinity.

Synthesis, In-Vitro, In-Vivo screening, and molecular docking of disubstituted aminothiazole derivatives and their selenium nanoparticles as potential antiparkinson agents

Neurological illnesses are among the leading causes of mortality across the world. In the present work, the synthesis of a new series of substituted aminothiazole derivatives (3a-e) as antiparkinsonian agents is reported. Furthermore, aminothiazoles 3a-e were used for in-situ synthesis of selenium nanoparticles 3a(SeNP)-3e(SeNP) to boost the CNS activities and potency. Selenium nanoparticles were confirmed using UV–Vis spectrophotometry, TEM, particle size distribution, and zeta potential. All selenium nano-sized forms elicited greater in-vitro inhibitory activity against both hMAO isoforms when compared to their corresponding normal-sized ones. Compound 3b was the most potent MAO-B inhibitor with an IC50 value of 0.11 µM. Its nano-sized form 3b(SeNP) showed improved hMAO-B inhibitory activity with an IC50 value of 0.033 µM which surpasses its normal-sized action (3b) by 70%. Molecular docking studies of compound 3b displayed interaction at the active sites of both hMAO-A and hMAO-B isoforms in an inhibitory mode similar to co-crystalized ligands. The antiparkinson effect of both 3b and 3b(SeNP) was further screened by using an in-vivo model of haloperidol-induced Parkinson's disease in rats. Behavioral tests in rats revealed that the nanoparticle formulation showed a superior effect on exploratory activity as an antiparkinsonian agent. Accordingly, this nanotechnology-based approach can be a promising lead for developing novel and potent treatments for neurodegenerative diseases.

Pyridazinone-substituted Benzenesulfonamides Demonstrate Inhibition of Monoamine Oxidase

Background: The monoamine oxidase (MAO) enzymes are important drug targets. Inhibitors of MAO-A and MAO-B have been used to treat the symptoms of depression and Parkinson’s disease. Methods: A series of seventeen pyridazinone-substituted benzenesulfonamides was synthesized and evaluated as potential inhibitors of human MAO-A and MAO-B. This study is a continuation of our interest in the pharmacological activities of sulfonamide compounds. Results: Among the compounds evaluated, only 10 and 18 demonstrated appreciable inhibition of MAOB with IC50 values of 2.90 and 4.36 μM, respectively. None of the benzenesulfonamides inhibited the MAO-A isoform. Potential binding orientations and interactions of 10 and 18 with the active site of MAO-B were investigated by computational approaches. Conclusion: Although these potencies are modest, this study is the first report on MAO inhibition by this class of compounds. Active MAO-B inhibitors may serve as leads for the future discovery of therapeutic agents for neurodegenerative disorders, such as Parkinson’s disease.

A Comprehensive Review of the Docking Studies of Chalcone for the Development of Selective MAO-B Inhibitors.

Monoamine oxidase B is a crucial therapeutic target for neurodegenerative disorders like Alzheimer's and Parkinson's since they assist in disintegrating neurotransmitters such as dopamine in the brain. Pursuing efficacious monoamine oxidase B inhibitors is a hot topic, as contemporary therapeutic interventions have many shortcomings. Currently available FDA-approved monoamine oxidase inhibitors like safinamide, selegiline and rasagiline also have a variety of side effects like depression and insomnia. In the quest for a potent monoamine oxidase B inhibitor, sizeable, diverse chemical entities have been uncovered, including chalcones. Chalcone is a renowned structural framework that has been intensively explored for its monoamine oxidase B inhibitory activity.The structural resemblance of chalcone (1,3-diphenyl-2-propen-1-one) based compounds and 1,4-diphenyl- 2-butene, a recognized MAO-B inhibitor, accounts for their MAO-B inhibitory activity. Therefore, multiple revisions to the chalcone scaffold have been attempted by the researchers to scrutinize the implications of substitutions onthe molecule's potency. In this work, we outline the docking investigation results of various chalcone analogues with monoamine oxidase B available in the literature until now to understand the interaction modes and influence of substituents. Here we focused on the interactions between reported chalcone derivatives and the active site of monoamine oxidase B and the influence of substitutions on those interactions. Detailed images illustrating the interactions and impact of the substituents or structural modifications on these interactions were used to support the docking results.

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice.

Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely understood, but we and others have previously shown that oxidative stress plays an important role. In particular, we have demonstrated that inhibition of mitochondrial monoamine oxidases could improve some functional and biohumoral markers of the pathology. In the present study we report the use of dystrophic mdx mice to evaluate the efficacy of a dual monoamine oxidase B (MAO-B)/semicarbazide-sensitive amine oxidase (SSAO) inhibitor, PXS-5131, in reducing inflammation and fibrosis and improving muscle function. We found that a one-month treatment starting at three months of age was able to decrease reactive oxygen species (ROS) production, fibrosis, and inflammatory infiltrate in the tibialis anterior (TA) and diaphragm muscles. Importantly, we also observed a marked improvement in the capacity of the gastrocnemius muscle to maintain its force when challenged with eccentric contractions. Upon performing a bulk RNA-seq analysis, PXS-5131 treatment affected the expression of genes involved in inflammatory processes and tissue remodeling. We also studied the effect of prolonged treatment in older dystrophic mice, and found that a three-month administration of PXS-5131 was able to greatly reduce the progression of fibrosis not only in the diaphragm but also in the heart. Taken together, these results suggest that PXS-5131 is an effective inhibitor of fibrosis and inflammation in dystrophic muscles, a finding that could open a new therapeutic avenue for DMD patients.

Synthesis and Monoamine Oxidase Inhibitory Activity of Halogenated Flavones.

Small molecule neurotransmitters containing amines are metabolized by monoamine oxidase (MAO) in the nervous system. Monoamine oxidase inhibitors are a valuable class of drugs prescribed for the management of neurological disorders, including depression. A series of halogenated flavonoids similar to the dietary flavonoid acacetin were designed as selective MAO-B inhibitors. MAO-A and -B inhibition of 36 halogenated flavones were tested. The halogens (fluorine and chlorine) were placed at positions 5 and 7 on ring A of the flavone scaffold. All compounds were selective MAO-B inhibitors with micro- and nanomolar IC50 values. Compounds 9f, 10a-c, 11a-c, 11g,h, and 11l displayed inhibitory activity toward MAO-B with IC50 values between 16 to 74 nM. We conclude that halogenated flavonoids are promising molecules in pursuit of developing new agents for neurological disorders.

Prescribing medications for Parkinson's: part two

Around 10 million people worldwide have Parkinson's and in the UK the estimated figure is 153 000. The condition is characterised by motor symptoms including tremors, stiffness, slowness, balance problems and/or gait disorders, but people can develop a wide range of associated psychological and physical problems. Treatment for Parkinson's includes a combination of multidisciplinary input from specialists such as physiotherapy, speech and language therapy and occupational therapy, alongside the use of recognised medication regimens. Most first-line medication requires titration and is started at a low dose and increased gradually, to reduce the risk of side effects and to monitor response to treatment. Medications for Parkinson's are complex to manage, and many have side effects that could affect patient concordance. Any prescribing decisions should be discussed with the person with Parkinson's and their family members. There are a variety of medications available to manage motor and non-motor symptoms in Parkinson's, but this article will focus on levodopa, dopamine agonists, MAO-B inhibitors and catechol-O-methyltransferase inhibitors.