Selective Monoamine Oxidase Research Articles

The State of the Art of Pyrazole Derivatives as Monoamine Oxidase Inhibitors and Antidepressant/Anticonvulsant Agents

Monoamine oxidase plays a significant role in the control of intracellular concentration of monoaminergic neurotransmitters or neuromodulators and dietary amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional and other brain functions. The development of human MAO inhibitors led to important breakthroughs in the therapy of several neuropsychiatric disorders. Different families of heterocycles containing 2 or 4 nitrogen atoms have been used as scaffolds for synthesizing selective monoamine oxidase inhibitors, but the early period of the MAO-inhibitors started with hydrazine derivatives. Pyrazole, pyrazoline, and pyrazolidine derivatives can be considered as a cyclic hydrazine moiety. This scaffold also displayed promising antidepressant and anticonvulsant properties as demonstrated by different and established animal models. Diversely substituted pyrazoles, embedded with a variety of functional groups, are important biological agents and a significant amount of research activity has been directed towards this chemical class.

Irreversible Inhibition of Monoamine Oxidase B by the Antiparkinsonian Medicines Rasagiline and Selegiline: A Computational Study

AbstractWe used quantum‐chemical methods to study seven possible mechanisms of monoamine oxidase (MAO) inhibition by acetylenic inhibitors, considering neutral, cationic, anionic and radical mechanisms. MAO is a flavoenzyme responsible for the metabolism of the important neurotransmitters noradrenaline, serotonin and dopamine. It exists in two isoforms: MAO A and MAO B. Selective MAO A inhibitors are used in the treatment of depression, whereas selective MAO B inhibitors such as rasagiline and selegiline are used to relieve symptoms of Parkinson disease. Rasagiline and selegiline are irreversible MAO B inhibitors, each forming a covalent bond with the enzyme's flavin adenine dinucleotide (FAD) cofactor upon inhibition. Although widely used, they both exhibit numerous adverse effects. Our calculations, performed at the B3LYP/6‐311++G(2d,2p)//B3LYP/6‐31+G(d) level of theory, with application of the CPCM solvent reaction field with ϵ = 4 to mimic the polar environment, found that a polar anionic mechanism, involving deprotonation of the inhibitor molecule at the terminal acetylene carbon atom, is the most plausible. The calculated free energies of activation for rasagiline and selegiline by this mechanistic pathway are 19.9 and 23.7 kcal mol–1, respectively, in very good agreement withexperimentally determined values of 20.8 and 21.3 kcal mol–1,respectively. Together with additional experimental and theoretical work, the results presented here could lead to better understanding of the nature of MAO inhibition and possible design of new antiparkinsonians as improved MAO B inhibitors. Some ideas on the strategy to achieve that and perspectives for future work are also given.

Synthesis and Study of a Series of 3-Arylcoumarins as Potent and Selective Monoamine Oxidase B Inhibitors

New series of 6-substituted-3-arylcoumarins displaying several alkyl, hydroxyl, halogen, and alkoxy groups in the two benzene rings have been designed, synthesized, and evaluated in vitro as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Most of the studied compounds showed a high affinity and selectivity to the hMAO-B isoenzyme, with IC(50) values on nanomolar and picomolar range. Ten of the 22 described compounds displayed higher MAO-B inhibitory activity and selectivity than selegiline. Coumarin 7 is the most active compound of this series, being 64 times more active than selegiline and also showing the highest hMAO-B specificity. In addition, docking experiments were carried out on hMAO-A and h-MAO-B structures. This study provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of this 3-arylcoumarin scaffold.

Pathological gambling in Parkinson's disease—a review of the literature

The prevalence of pathological gambling is 3.4% to 6% in treated Parkinson's disease, which is higher than the background population rate. In this review we discuss current evidence to indicate that dopamine agonists are much more likely to trigger this behavior than either L-dopa or selective monoamine oxidase B inhibitor monotherapy. New insights from recent behavioral and functional imaging studies and possible treatment approaches are also covered. A PubMed literature search using the terms "gambling" and "Parkinson's disease," "impulse control disorder," "impulsive compulsive behaviour," "dopamine agonist," of individual dopamine agonists, and of ongoing drug trials, using http://www.clinicaltrials.gov, was carried out for the period up to January 2011.

Rasagiline-induced Delay of Retinal Ganglion Cell Death in Experimental Glaucoma in Rats

To evaluate the neuroprotective effect of rasagiline (N-propargyl-1 (R)-aminoindan), a selective monoamine oxidase inhibitor, on the survival of retinal ganglion cells (RGCs) in glaucomatous rat eyes. Rasagiline is an FDA approved anti-Parkinson disease drug with neuroprotective capabilities that were shown in many models of brain damage. The neuroprotective effect of daily intraperitoneal (IP) injections of rasagiline (0.5 mg/kg and 3 mg/kg) was evaluated and compared with saline injections using the translimbal photocoagulation model of experimental glaucoma in Wistar rats. Intraocular pressure (IOP) was measured before and immediately after the laser treatment, and then weekly. Seven weeks after the induction of glaucoma, the animals were killed, the eyes were enucleated and the retinas were prepared as whole mounts. Fluoro-gold had been injected into the superior colliculus 10 days before enucleation, and RGC survival was evaluated by counting the surviving labeled RGCs in a masked way. All rats (n=29) displayed significant IOP elevation and RGC damage. Seven weeks after the induction of glaucoma, the mean RGC survival was 43±8% in the rasagiline 3 mg/kg-treated group and 43±9% in the rasagiline 0.5 mg/kg-treated group compared with 23%±4% in the saline-treated (control) group (P=0.01 and P=0.02, respectively). Systemic treatment with rasagiline significantly enhances the survival of RGCs in experimental glaucoma.

The effects of rasagiline on cognitive deficits in Parkinson's disease patients without dementia: A randomized, double‐blind, placebo‐controlled, multicenter study

Cognitive impairment can occur at all stages of Parkinson's disease. Rasagiline is a selective monoamine oxidase type-B inhibitor that enhances central dopaminergic transmission. Dopamine is thought to be involved in certain cognitive processes such as working memory. We assessed the effects of rasagiline on cognitive deficits in cognitively impaired, nondemented patients with Parkinson's disease. This was a randomized, double-blind, placebo-controlled prospective study. Patients with Parkinson's disease receiving stable dopaminergic treatment were assigned to receive rasagiline 1 mg/day or placebo for 3 months. Patients were eligible if they had impairment in 2 of 4 cognitive domains (attention, executive functions, memory, visuospatial functions) in the screening neuropsychological tests, yet did not fulfill criteria for Parkinson's disease dementia. Fifty-five patients were randomized; 48 patients completed the study. Patients in the rasagiline group showed significant improvement in digit span-backward compared with the placebo group (P = .04), with trends favoring rasagiline in digit span total and digit-ordering tests. Verbal fluency total score showed a significant difference in favor of rasagiline (P = .038), with trends favoring rasagiline in semantic fluency test and Stroop spontaneous corrections. The composite cognitive domain Z scores revealed a significant difference in favor of rasagiline compared with placebo in the attentional Z score (P < .005). There were no significant differences between the 2 groups in the other cognitive tests or cognitive domain Z scores. The monoamine oxidase type-B inhibitor rasagiline may exert beneficial effects on certain aspects of attention and executive functions in nondemented patients with Parkinson's disease with cognitive impairment.

Development of selective and reversible pyrazoline based MAO-B inhibitors: Virtual screening, synthesis and biological evaluation

In an effort to develop selective MAO (monoamine oxidase) B inhibitors, structure based virtual screening was initiated on an in-house library. Top 10 HITS were synthesized and evaluated for MAO (A and B) inhibitory activity, both against human and rat enzymes. All the compounds were found selective, reversible and active in nM range (100 times more potent than selegeline) towards MAO-B. Outstanding co-relation between predicted and experimental K(i) values were observed.

ChemInform Abstract: 5-Aryl-1,3,4-oxadiazol-2(3H)-one Derivatives and Sulfur Analogues as New Selective and Competitive Monoamine Oxidase Type B Inhibitors.

Abstract Eighteen new 5-aryl-1,3,4-oxadiazol-2(3H)-one derivatives and sulfur analogues were prepared and evaluated in vitro for their inhibitory properties on monoamine oxidase (MAO) types A and B. The most active compounds in these series acted preferentially against MAO B with IC50 values in the range of 1.8-0.056 μM. The 5-(4-biphenylyl)-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one 23 and its oxadiazolethione analogue 33 were found to act as potent, selective and competitive MAO B inhibitors with a slight slow-binding character. Both compounds inhibited MAO A in a classical competitive manner. According to their Ki (MAO B) values of 2.6 and 4 × 10−8 M, respectively, and their Ki (MAO A)/Ki (MAO B) ratios of 270 and 500, respectively, 23 and 33 can be placed among the most active and selective competitive MAO B inhibitors known up to now. The structure-activity relationships are discussed.

Propargylamine Containing Compounds as Modulators of Proteolytic Cleavage of Amyloid Protein Precursor: Involvement of MAPK and PKC Activation

The anti-Parkinsonian, irreversible, selective monoamine oxidase (MAO)-B inhibitors, selegiline (deprenyl, (R)-N-methyl-N-(1-phenylpropan-2-yl) prop-2-yn-1-amine) and rasagiline (Azilect, N-propargyl-1(R)-aminoindan), have been proven to possess neuroprotective/neurorestorative activities in cell cultures and animal models of neurodegenerative diseases. Structure-activity studies provide evidence that neuroprotection is associated with some intrinsic pharmacological action of the propargylamine moiety in these drugs. This indication and recent therapeutic approaches, entailing new drug candidates possessing diverse pharmacological properties and acting on multiple targets, have stimulated the development of two multifunctional chimeric propargylamine-derivatives: 1) ladostigil (TV3326, [(N-propargyl-(3R) 1-(R)-aminoindan-5yl)-ethyl methyl carbamate)], which combines the pharmacophore of rasagiline, with the carbamate moiety of the cholinesterase inhibitor rivastigmine, as a potential treatment for Alzheimer's disease and Lewy body disease; and 2) M30 5-[(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], where the propargylamine moiety of rasagiline was embedded onto the backbone of the neuroprotective and brain permeable iron chelator 8-hydroxyquinoline-derivative, VK28 as a potential treatment for various neurodegenerative disorders. Both multifunctional propargylamine-derivatives were found to possess neuroprotective and anti-apoptotic properties. An additional and new neuroprotective effect, shared by the propargylamine-derivative compounds, is related to their ability to regulate the processing of amyloid-beta protein precursor (AbetaPP) by the non-amyloidogenic alpha-secretase pathway. This effect was shown to involve activation of p42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathway. This review will summarize and discuss current research, focused on the effect of propargylamine-related derivatives on the proteolytic processing of AbetaPP and signal transduction mechanisms.

2-Arylthiomorpholine derivatives as potent and selective monoamine oxidase B inhibitors

2-Arylthiomorpholine and 2-arylthiomorpholin-5-one derivatives, designed as rigid and/or non-basic phenylethylamine analogues, were evaluated as rat and human monoamine oxidase inhibitors. Molecular docking provided insight into the binding mode of these inhibitors and rationalized their different potencies. Making the phenylethylamine scaffold rigid by fixing the amine chain in an extended six-membered ring conformation increased MAO-B (but not MAO-A) inhibitory activity relative to the more flexible α-methylated derivative. The presence of a basic nitrogen atom is not a prerequisite in either MAO-A or MAO-B. The best Ki values were in the 10−8M range, with selectivities towards human MAO-B exceeding 2000-fold.

Design of novel nicotinamides as potent and selective monoamine oxidase a inhibitors

A series of N-(2-morpholinoethyl)nicotinamide (1–13) and N-(3-morpholinopropyl)nicotinamide derivatives (14–26) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. Most of these synthesized compounds proved to be potent, and selective inhibitors of MAO-A rather than of MAO-B. 5-Chloro-6-hydroxy-N-(2-morpholinoethyl)nicotinamide (13) displayed the highest MAO-A inhibitory potency (IC50=0.045μM) and a good selectivity. 2-Bromo-N-(2-morpholinoethyl)nicotinamide (3) was the most potent MAO-B inhibitor with the IC50 value of 0.32μM, but it was not selective. Molecular dockings of compound 13 were performed in order to give structural insights regarding the MAO-A selectivity.

Discovery of a Novel Class of Potent Coumarin Monoamine Oxidase B Inhibitors: Development and Biopharmacological Profiling of 7-[(3-Chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one Methanesulfonate (NW-1772) as a Highly Potent, Selective, Reversible, and Orally Active Monoamine Oxidase B Inhibitor

In an effort to discover novel selective monoamine oxidase (MAO) B inhibitors with favorable physicochemical and pharmacokinetic profiles, 7-[(m-halogeno)benzyloxy]coumarins bearing properly selected polar substituents at position 4 were designed, synthesized, and evaluated as MAO inhibitors. Several compounds with MAO-B inhibitory activity in the nanomolar range and excellent MAO-B selectivity (selectivity index SI > 400) were identified. Structure-affinity relationships and docking simulations provided valuable insights into the enzyme-inhibitor binding interactions at position 4, which has been poorly explored. Furthermore, computational and experimental studies led to the identification and biopharmacological characterization of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate 22b (NW-1772) as an in vitro and in vivo potent and selective MAO-B inhibitor, with rapid blood-brain barrier penetration, short-acting and reversible inhibitory activity, slight inhibition of selected cytochrome P450s, and low in vitro toxicity. On the basis of this preliminary preclinical profile, inhibitor 22b might be viewed as a promising clinical candidate for the treatment of neurodegenerative diseases.

Prevention of psychiatric illness in the elderly, I: Path to prevention of dementia

Prevention of psychiatric illness in the elderly, I: Path to prevention of dementia

Selegiline transdermal system: a novel treatment option for major depressive disorder

Background: The use of monoamine oxidase inhibitors has declined owing to the risk of hypertensive crisis following the consumption of tyramine-rich foods and the consequent need for dietary tyramine restriction. However, owing to their superior efficacy in treating depression, continued efforts have been made to develop more selective and reversible monoamine oxidase inhibitors. Oral selegiline, at low doses, is a selective monoamine oxidase B (MAO-B) inhibitor, but at higher doses it loses its selectivity and can potentially interact with tyramine. Unfortunately, antidepressant effects of selegiline have been observed only at higher doses. The selegiline transdermal system was developed to deliver sustained selegiline blood concentrations sufficient to selectively inhibit MAO-A and MAO-B in the brain, producing antidepressant effects, without substantially inhibiting MAO-A in the gastrointestinal tract, thereby reducing the risk of hypertensive crisis. Objectives: This article reviews the basic pharmacology, as well as efficacy and safety data of selegiline transdermal system for the treatment of depression. Conclusions: Selegiline transdermal system is safe and effective in treating major depressive disorder at the dose range of 6 – 12 mg/24 h, without the need for dietary precautions at the 6 mg/24 h dose. No cases of hypertensive crisis were reported in clinical trials, even without dietary restrictions.

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drugs, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuroprotective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine. A second derivative of rasagiline, M-30 was developed by amalgamating the propargyl moiety of rasagiline into the skeleton of our novel brain permeable neuroprotective iron chelator, VK-28. Preclinical experiments showed that both compounds have anti-Alzheimer's disease activities and thus, the clinical development is oriented toward treatment of this type of dementia. This review discusses the multimodal effects of two rasagiline-containing hybrid molecules, namely ladostigil and M-30, concerning their neuroprotective molecular mechanisms in vivo and in vitro, including regulation of amyloid precursor protein processing, activation of protein kinase C, and mitogen-activated protein kinase signaling pathways, inhibition of cell death markers and upregulation of neurotrophic factors. Altogether, these scientific findings make these multifunctional compounds potentially valuable drugs for the treatment of Alzheimer's disease.

Neuroprotection by rasagiline in thiamine deficient rats

Thiamine deficiency (TD) in rats is a model of chronic impairment of oxidative metabolism leading to neuronal loss. TD rats exhibit neuropathological, behavioral and cognitive abnormalities. The aim of this study was to use this syndrome to assess the neuroprotective potential of drugs in a whole animal model. TD was produced in rats using the following protocol: thiamine deficient diet, daily injections of the central thiamine antagonist, pyrithiamine (0.5 mg/kg), and the test drugs, the selective monoamine oxidase (MAO) B inhibitors, rasagiline (1 or 3 mg/kg/day) and selegiline (2.4 or 8 mg/kg/day). Normal rats and untreated TD rats served as controls. Upon the appearance of neurological symptoms, the TD protocol was suspended, rats were transferred to a regular diet, pyrithiamine and test drug injections were terminated and rats were injected with 3 daily doses of thiamine (100 mg/kg). Neuroprotective potential was assessed by: general behavioral observations, cognitive testing using the Morris water maze and histopathological examination of the brains. Rasagiline but not selegiline significantly delayed the onset and severity of the neurological symptoms of TD. In the Morris water maze, TD-untreated rats displayed severe cognitive impairment while rasagiline-treated rats were similar to control rats and significantly different from TD-untreated rats. The effects were dose related. Selegiline treatment had no significant protective effect. TD-untreated brains displayed extensive gliotic and necrotic lesions mainly in the thalamus and posterior collicular nucleus, which were significantly reduced in the rasagiline-treated TD rats. These findings demonstrate significant neuroprotection by rasagiline with possible implications for clinical neurodegenerative disorders.

Orally disintegrating selegiline for the treatment of Parkinson's disease

The selective monoamine oxidase type B inhibitor selegiline is commonly administered as medical treatment to patients suffering from Parkinson's disease. The clinical value of conventional selegiline is, however, compromised by extensive first-pass metabolism, which reduces its bioavailability and leads to the production of possibly harmful methamfetamine metabolites. This review aims to evaluate a novel, orally disintegrating formulation of selegiline by examining scientific evidence from previous pharmacological and clinical studies. As a result of improved bioavailability, orally disintegrating selegiline can be administered at lower doses than conventional selegiline with similar clinical effect. It also leads to less variable selegiline blood concentrations and produces significantly less methamfetamine metabolites. We conclude that this novel formulation offers an interesting treatment option, especially for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.

Transtelephonic Home Blood Pressure to Assess the Monoamine Oxidase-B Inhibitor Rasagiline in Parkinson Disease

Monoamine oxidase inhibitors are associated with dietary tyramine interactions that can induce hypertensive crises. Rasagiline mesylate is a novel irreversible selective monoamine oxidase type B inhibitor for Parkinson disease that may have a low risk of interaction with dietary tyramine because of its selectivity. To study interactions of rasagiline with diets unrestricted in tyramine-containing foods, we incorporated transtelephonic, self-monitoring of the blood pressure (BP) into a randomized, placebo-controlled trial of rasagiline 0.5 and 1.0 mg daily in 414 levodopa-treated Parkinson patients with motor fluctuations. The proportion of patients with a systolic BP increase of >30 mm Hg was the primary BP end point. In 13 968 self-measured readings at baseline, the proportion of systolic BP values that increased by >30 mm Hg after a meal ranged from 9.5% to 12.9% in the 3 treatment groups. In 25 733 BPs obtained postrandomization, the proportion of values with a >30-mm Hg systolic postprandial increase was 15% in the placebo group, 15% in the rasagiline 0.5-mg group, and 11% in the rasagiline 1-mg group after 3 weeks of double-blind therapy and 13%, 14%, and 12%, respectively, after 26 weeks of treatment (P value was not significant for all of the comparisons among treatment groups). A postprandial increase in systolic BP to >180 mm Hg at any time after randomization was seen in 3.3%, 2.6%, and 2.9% of the placebo, 0.5-mg, and 1.0-mg rasagiline groups, respectively. These data demonstrate that rasagiline did not induce postprandial hypertension in patients with Parkinson disease who were on an unrestricted diet.

The neuroprotective effect of ladostigil against hydrogen peroxide-mediated cytotoxicity

The multifunctional, anti-Alzheimer drug, ladostigil (TV3326) [( N-propargyl-(3 R) aminoindan-5yl)-ethyl methyl carbamate] combines the neuroprotective effects of the anti-Parkinson drug, rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule. Ladostigil has been shown to possess potent antiapoptotic and neuroprotective activities in various oxidative insults in vitro and in vivo, such as prevention of the fall in mitochondrial membrane potential and regulation of Bcl-2 family proteins. In the present study, we demonstrate that ladostigil (1 μM) increased cell viability, associated with the increase of catalase activity and decrease of intracellular reactive oxygen species (ROS) production in human SH-SY5Y neuroblastoma cells exposed to (hydrogen peroxide) H 2O 2. Furthermore, ladostigil significantly elevated mRNA levels of the antioxidants enzymes, catalase, NAD(P)H quinone oxidoreductase 1 (NQO1) and peroxiredoxin 1 (Prx 1) in H 2O 2-treated SH-SY5Y cells. Chronic treatment with ladostigil (1 mg/kg gavage per day for 30 days) markedly up-regulated mRNA expression levels of various antioxidant enzymes in aged rat hippocampus (e.g. glutathione peroxidase precursor (GSHPX-P), glutathione S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PD)). These findings indicate that in addition to its multiple neuroprotective characteristics, ladostigil also possesses antioxidant properties, which might be beneficial for the treatment of oxidative stress (OS) in aging and age-associated neurodegenerative diseases.

Synthesis and Monoamine Oxidase Inhibitory Activities of 1‐Thiocarbamoyl‐3,5‐diphenyl‐4,5‐dihydro‐1H‐pyrazole Derivatives

Ten new 1-thiocarbamoyl-3-(phenyl and/or 4-substituted phenyl)-5-(3,4-dimethoxyphenyl and/or 2-chloro-3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole derivatives were synthesized by reacting 1,3-diphenylpropen-1-ones and thiosemicarbazide. The chemical structures of the compounds were verified by means of their IR, 1H-NMR, ESI-MS spectroscopic data and elementary analyses. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in-vitro tests. Monoamine oxidase was isolated and purified from the mitochondrial extracts of rat-liver homogenates and human platelets. Monoamine oxidase inhibitory activities of the compounds were compared with pargyline and clorgyline. Most of the compounds inhibited the total activity of rat liver homogenates. The monoamine oxidase-A inhibitory effects of 1-thiocarbamoyl-3-(4-methoxyphenyl)-5-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole and 1-thiocarbamoyl-3-(4-methoxyphenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazole were detected as potent as clorgyline. Selective and irreversible inhibition of rat liver monoamine oxidase-A by synthesized compounds have promising features for designing the new selective monoamine oxidase A inhibitors as potent and reliable anti-depressants in the future.