Reversible Monoamine Oxidase B Research Articles

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.

Design, synthesis, in-vitro, in-vivo and ex-vivo pharmacology of thiazolidine-2,4-dione derivatives as selective and reversible monoamine oxidase-B inhibitors

Neurodegenerative ailments are a diverse set of syndromes distinguished by gradual deterioration of the structure as well as functions of the central nervous system or peripheral nervous system. Alzheimer’s disease (AD) and Parkinson’s disease (PD) have no cure, common, and are high prevalent neurodegenerative pathologies. In current research, rationally designed thiazolidine-2,4-dione based analogs were synthesized and tested for their inhibition potential against two isoforms of monoamine oxidase (MAO-A / MAO-B). Structure activity relationships were explored. Pyridinyl and thiazolyl hydrazone derivative 43 and 44 with IC50 value of 0.013 µM and 0.008 µM (selectivity 228 / 226 times) exhibited higher potency than reference drug safinamide. Most active compounds showed BBB penetration in PAMPA in-vitro assay. Except nitro derivative 41, all compounds were non-neurotoxic in the studied concentration. Molecular docking studies supported the in-vitro experimental results and the selectivity by comparing the binding energy values against both MAO-A and MAO-B isoforms. All the results of current research suggest compounds 43 and 44 may serve as promising candidates for further research for treatment of neurodegenerative diseases.

Highly Efficient Radiosynthesis and Biological Evaluation of [18 F]Safinamide, a Radiolabelled Anti-Parkinsonian Drug for Positron Emission Tomography Imaging.

As an add-on drug approved for Parkinson's disease treatment, safinamide has multiple functions, such as selective and reversible monoamine oxidase-B inhibition, voltage-sensitive sodium/potassium channel blockage, and glutamate release inhibition. Meanwhile, safinamide shows tremendous therapeutic potential in the context of other central nervous system diseases (e. g. ischaemic stroke, amyotrophic lateral sclerosis, depression, etc.). In this work, [18 F]safinamide, which is safinamide labelled by the positron-emitting radionuclide [18 F]fluorine, was synthesized automatically based on iodonium ylide precursors with high radiochemical yield and high molar activity. Density functional theory was applied to calculate the Gibbs free energy change during iodonium ylide-mediated fluorination and to interpret the effect of tetraethylammonium (TEA+ ) as the counter cation in these reactions to improve the nucleophilicity of [18 F/19 F]fluoride. In addition, positron emission tomography studies on Sprague Dawley rats were carried out to determine the imaging characteristics, pharmacokinetics, and metabolism of the [18 F]safinamide radiotracer. The results displayed the complete biodistribution of the radiotracer, especially in rat brains, and revealed that [18 F]safinamide has moderate brain uptake, rapid and reversible binding kinetics, and good stability.

Collective Expert Perspectives on the Use of Safinamide as Adjunctive Therapy for Parkinson's Disease: Online-Based Delphi Survey.

Background Safinamide is a selective, reversible monoamine oxidase-B inhibitor with a sodium channel inhibitory effect. Published clinical evidence supports safinamide as an effective therapy for Parkinson's disease (PD) with wearing-off. However, to date, no consensus recommendations have been available to guide physicians in Asia on the optimal use of safinamide in clinical practice. To summarize opinions on the optimal patient profile and methods of using safinamide in common clinical scenarios, Japanese movement disorder specialists with expertise in PD investigated the perspectives of neurologists and neurosurgeons. Methods The Delphi panel approach was used to summarize the opinions of panelists. The panel comprised doctors from Japan with extensive clinical practice experience in the use of safinamide (n = 46 at the final round). The consensus was defined as 80% or more agreement between panelists for each scenario at the final round. Results There was a high level of agreement that patients with the following symptoms are suitable for safinamide treatment such as bradykinesia (100%), rigidity (95.7%), and/or gait disorder (89.1%) based on motor symptoms and PD-related pain (97.8%) and/or depression or apathy (93.5%) based on non-motor symptoms. Morning-off (95.7%), but not dyskinesia (71.7%), also reached consensus. The use of high-dose safinamide (100 mg/day) was recommended when the improvement in PD symptoms is insufficient and increasing the doses of other anti-PD medications is difficult (97.8%) or when the abovementioned non-motor symptoms adversely affect daily life (93.5%). Conclusions This report provides expert perspectives on the use of safinamide for a wide range of clinical scenarios in Japan.

The Role of Chirality of [18F]SMBT-1 in Imaging of Monoamine Oxidase-B.

(S)-(2-Methylpyrid-5-yl)-6-[(3-[18F]fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) was recently developed as a novel class of selective and reversible monoamine oxidase-B (MAO-B) tracers for in vivo imaging of reactive astrogliosis via positron emission tomography. To investigate the effect of the chirality of [18F]SMBT-1 on tracer performance, we synthesized (S)-[18F]6 ([18F]SMBT-1) and (R)-[18F]6 and compared their binding properties, pharmacokinetics, and metabolism. (S)-6 showed higher binding affinity to MAO-B and lower binding affinity to MAO-A than (R)-6, demonstrating a higher selectivity ratio (MAO-B/MAO-A). A pharmacokinetic study in mice demonstrated that both (S)-[18F]6 and (R)-[18F]6 showed sufficient initial brain uptake. However, (S)-[18F]6 was cleared significantly faster from the body. An abundant sulfoconjugate metabolite M2 was observed in plasma for (S)-[18F]6 but not for (R)-[18F]6. In vitro sulfation assays confirmed that (S)-6 was more reactive than (R)-6, consistent with the in vivo findings. Mefenamic acid, a selective sulfotransferase 1A1 (SULT1A1) inhibitor, strongly inhibited the in vitro sulfation of (S)-6 by mouse liver fractions, human liver cytosol fractions, and human recombinant SULT1A1 enzyme. Genetic polymorphisms of SULT1A1 did not affect the sulfation of (S)-6 in vitro. In conclusion, (S)-[18F]6 had a more favorable binding affinity and binding selectivity for MAO-B than (R)-[18F]6. Additionally, (S)-[18F]6 also possessed better pharmacological and metabolic properties than (R)-[18F]6. These results suggest that (S)-[18F]6 ([18F]SMBT-1) is a promising candidate for application in the imaging of MAO-B in vivo.

Development of methylthiosemicarbazones as new reversible monoamine oxidase-B inhibitors for the treatment of Parkinson’s disease

Selective monoamine oxidase-B (MAO-B) inhibition is an attractive subject for the treatment of Parkinson’s disease (PD). In the current study, we synthesized some selected derivatives of methylthiosemicarbazones and investigated their MAOs and acetylcholinesterase (AChE) inhibitory activities. Among the series synthesized, compounds SM5, SM4, and SM9 most inhibited MAO-B with IC50 values of 5.48, 7.06, and 8.03 µM, respectively. All compounds tested weakly inhibited MAO-A at 10 µM with the residual activities of >50%. Compound SM5 had the highest selectivity index (SI) value for MAO-B (>7.30), followed by SM4 (>5.67). Kinetic experiments revealed that SM5 competitively inhibited MAO-B, with a mean Ki value of 2.39 ± 0.15 µM. Reversibility experiments showed that SM5 reversibly inhibited MAO-B, and 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that SM5 was not toxic to Vero cells (IC50 = 198.96 µg/mL). The SM5/MAO-B interaction was ascertained by molecular docking and dynamics studies. The study shows that SM5 competitively inhibits MAO-B in a reversible, moderate selective manner, and that it is non-toxic to Vero cells. Communicated by Ramaswamy H. Sarma

Synthesis and preclinical evaluation of [18F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B.

Carbon-11 labeled SL25.1188 is a promising reversible monoamine oxidase-B (MAO-B) radioligand that was recently translated for human positron emission tomography (PET) imaging. Herein, we report the development of a novel fluorinated derivative, namely, [18F](S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one ([18F]FSL25.1188; [18F]6), as a candidate 18F-labeled MAO-B radioligand, and, its subsequent preclinical evaluation in non-human primates (NHP). [18F]6 was produced and isolated (>6 GBq) with high radiochemical purity (>99%), and molar activity (>100 GBq/µmol at time of injection). Autoradiography studies conducted in post-mortem human brain sections revealed [18F]6 binding in MAO-B rich regions. PET imaging study of [18F]6 in NHP showed high brain uptake (SUV > 2.5) as well as a regional brain radioactivity distribution in accordance with MAO-B expression. [18F]6 displayed favorable in vivo kinetics, with an early peak in the time-activity curve followed by progressive wash-out from the NHP brain. Specificity of [18F]6 was investigated in a pre-treatment study with l-deprenyl (1.0 mg/kg) wherein reduced radioligand uptake was observed in all MAO-B rich regions. Results from the current preclinical investigation suggests [18F]6 is a promising MAO-B PET radioligand. Further evaluation of [18F]6 and structurally related 18F-analogs are underway to identify an optimized candidate for clinical research studies.

Safinamide: A Review in Parkinson's Disease.

Safinamide (Xadago®) is an orally active, selective, reversible monoamine oxidase-B inhibitor with both dopaminergic and non-dopaminergic (glutamatergic) properties. In the EU, safinamide is approved for the treatment of mid- to late-stage fluctuating Parkinson's disease (PD) as add-on therapy to a stable dose of levodopa alone or in combination with other PD medications. Safinamide 50-100mg/day administered as a fixed or flexible dose significantly increased daily 'on' time without dyskinesia (primary endpoint) in patients with mid- to late-stage PD with motor fluctuations in 24-week, placebo-controlled clinical trials. Other outcomes, including motor function, overall clinical status and health-related quality of life, were also generally improved with safinamide. Furthermore, in an 18-month extension of one study, although dyskinesia (primary endpoint) was not significantly improved with safinamide relative to placebo, treatment benefits in other outcomes were generally sustained over 24months of treatment. Safinamide was generally well tolerated in clinical trials; dyskinesia was the most common adverse event. Although further studies are needed, including comparative and long-term studies, current evidence indicates that safinamide extends the treatment options available for use as add-on therapy to levodopa and other PD medications in patients with mid- to late-stage PD experiencing motor fluctuations.

Clinical Pharmacokinetics and Pharmacodynamics of Safinamide.

The symptoms of Parkinson's disease (PD) reflect disruptions of a number of brain neurotransmitter systems of varying type and degree. Pharmacological agents with multiple neurochemical mechanisms of action are therefore promising candidates for countering these problems and providing comprehensive symptomatic relief for patients. The pharmacological profile of safinamide includes reversible monoamine oxidaseB inhibition, blockage of voltage-dependent Na+ channels, modulation of Ca2+ channels, and inhibition of glutamate release. Safinamide is administered once daily at oral doses of 50-100mg; it is well-tolerated and safe. Clinical trials have found that it ameliorates motor symptoms when added to established levodopa or single dopamine receptor agonist therapy. The future role of safinamide in PD may be that it enables a reduction in the dosage of dopamine replacement therapies, thereby reducing the adverse effects associated with these treatments. The clinical convenience (once-daily administration), safety, and tolerability of safinamide are better than those of dopamine receptor agonists. The introduction of safinamide reflects a change of approach to drug development for anti-parkinsonian agents in that its broad spectrum of action corresponds to the multiple heterogeneous alterations of brain neurochemistry in PD, rather than being targeted at a single receptor type or neurochemical process. Safinamide is a promising new instrument for the effective symptomatic therapy of PD.

Emerging approaches in Parkinson's disease - adjunctive role of safinamide.

Ongoing neuronal death in Parkinson’s disease (PD) causes an altered neurotransmission of various biogenic amines, particularly dopamine. As these changes do not follow a distinct pattern, they vary individually, and are differently pronounced. As a result, a heterogeneous onset of motor and nonmotor features occurs in each patient with PD during the whole course of the disease. PD actually describes a set of distinct diseases that manifest themselves in clinical syndromes with certain similarities but also great differences. This clinical picture responds to drugs with a broad spectrum of modes of actions better than to compounds with an exclusive focus on specific receptor subtypes. Therefore, safinamide is an ideal candidate for treatment of patients with PD, since its pharmacological profile includes reversible monoamine oxidase-B inhibition, blockade of voltage-dependent sodium channels, modulation of calcium channels, and inhibition of glutamate release. Safinamide is applied only once daily. Its oral dose ranges from 50 to 100 mg. Safinamide was well tolerated and safe in the clinical development program that demonstrated the amelioration of motor symptoms and OFF phenomena by safinamide when combined with dopamine agonists or levodopa. In the real world of maintenance of patients with PD, effects of safinamide application resemble therapy with classical monoamine oxidase inhibitors or amantadine in combination with other dopamine-substituting drugs. Safinamide is becoming increasingly available in the EU despite complex approval and pricing scenarios.

Docking of novel reversible monoamine oxidase-B inhibitors: efficient prediction of ligand binding sites and estimation of inhibitors thermodynamic properties

Monoamine oxidase (MAO, EC 1.4.3.4) is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known target for antidepressant, Parkinson's disease and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for molecular modeling studies. In this research 12 reversible and MAO-B selective inhibitors have been docked computationally to the active site of the MAO-B enzyme. AutoDock 3.0.5 was employed to perform the automated molecular docking. The result of docking studies generated thermodynamic properties, such as free energy of bindings (DeltaG(b)) and inhibition constants (K (i)) for the inhibitors. Moreover, 3D pictures of inhibitor-enzyme complexes afforded valuable data regarding the binding orientation of each inhibitor in the active site of MAO-B.

In vitro effects on monoamine uptake and release by the reversible monoamine oxidase-B inhibitors Lazabemide and N-(2-aminoethyl)- p-chlorobenzamide: A comparison with l-deprenyl

To investigate whether the reversible monoamine oxidase-B (MAO-B) inhibitors lazabemide and Ro 16–6491 have any additional effect on monoamine uptake and release, in vitro experiments were performed on rat forebrain synaptosomes and blood platelets. The effects of the two drugs were compared with those of l-deprenyl, the well-known irreversible MAO-B inhibitor which is reported to affect amine uptake. Both lazabemide and Ro 16–6491 behaved as weak inhibitors of [ 3H]monoamine uptake by synaptosomes, with a similar rank order of potency for amine uptake inhibition (noradrenaline (NA) ⩾ 5-hydroxytryptamine (5 HT) dopamine (DA)). The ic 50 values for lazabemide and Ro 16–6491, respectively, were: 86 μM and 90 μM for NA uptake; 123 μM and 90 μM for 5HT uptake; > 500 μM and > 1000 μM for DA uptake. l-Deprenyl (rank order of inhibitory potency: NA > DA > 5 HT) was four to 10 times more potent than either compound in inhibiting [ 3H]catecholamine uptake (IC 50 = NA 23 μM, DA 109 μM), and two to three times less potent in inhibiting 5 HT uptake ( ic 50 233 μM). Lazabemide and Ro 16–6491 also differed from l-deprenyl in their ability to induce release of endogenous monoamines from synaptosomes. Thus, Ro 16–6491 (500 μM) induced a greater 5 HT release than did l-deprenyl, but was less effective than l-deprenyl in releasing DA. On the contrary, lazabemide was almost completely inactive on either 5 HT and DA release. The differential effect of the three MAO-B inhibitors on synaptosome 5 HT uptake and release was confirmed by [ 14C]5HT uptake and liberation experiments with isolated rat platelets. The data indicate that the reversible MAO-B inhibitors lazabemide and Ro 16–6491 at relatively high concentrations possess amine uptake-inhibiting properties. With regard to the effects examined, lazabemide markedly differs from l-deprenyl since it does not interfere with DA uptake nor induce amine release from synaptosomes.

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia.

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP+), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP+ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 microM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 microM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 microM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.

A study of the biological pharmacology of IFO, a new selective and reversible monoamine oxidase-B inhibitor.

3-[4-[3-(1H-Imidazol-1-yl)propoxy]phenyl]-5-trifluoromethyl-1,2,4- oxadiazole (IFO), designed to be a novel selective inhibitor of monoamine oxidase (MAO), showed highly selective inhibition for type-B (MAO-B); its IC50 was approximately > 200 microM and 30 nM for type-A (MAO-A) and MAO-B, respectively, in the standard assay using mitochondrial preparations from rat brain or liver. The in vitro MAO-B inhibition by IFO was time-independent, non-competitive and tight-binding; and furthermore, in the presence of sodium cholate its inhibition was not tight-binding and was reversible. Oral administration of IFO (0.5-100 mg/kg) produced a dose-dependent MAO-B inhibition in mouse brain; its ED50 (p.o., 1 hr) was 1.6 mg/kg, while L-deprenyl inhibited the enzyme with the ED50 of approximately 8.0 mg/kg. The ED50 for MAO-A was > 100 mg/kg for either IFO and L-deprenyl. The MAO inhibitive effect of IFO in mouse liver was the same as that in the brain, but that of L-deprenyl in mouse liver was different from that in the brain as shown by the ED50 values of 35 mg/kg and 0.6 mg/kg for MAO-A and MAO-B, respectively. In mice, IFO increased the striatal concentrations of 2-phenylethylamine (2-PEA) and showed almost the same protective efficacy as L-deprenyl against the lethality and striatal dopamine (DA) depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results indicate that IFO appears to be a potent inhibitor of MAO-B in mouse brain.

A Study of the Biological Pharmacology of IFO, a New Selective and Reversible Monoamine Oxidase-B Inhibitor

A Study of the Biological Pharmacology of IFO, a New Selective and Reversible Monoamine Oxidase-B Inhibitor

Transformation of heterocyclic reversible monoamine oxidase-B inactivators into irreversible inactivators by N-methylation.

3-[4-[(3-Chlorophenyl)methoxy]phenyl]-5-[(methylamino)methyl]- 2-oxazolidinone (1) is a secondary amine known to be a potent time-dependent irreversible inactivator of monoamine oxidase B (MAO-B). The primary amine analogues of derivatives of 1, as well as of the corresponding dihydrofuranone and pyrrolidinone, had been shown to be time-dependent, but reversible, inhibitors of MAO-B. Here it is shown that the primary amine analogue of 1 is a time-dependent reversible inhibitor of MAO-B and that the secondary and tertiary amine analogues of the corresponding oxazolidinone, dihydrofuranone, and pyrrolidinone are time-dependent irreversible inhibitors of MAO-B. The reaction leading to the irreversible enzyme adduct formation with 1 can be reversed by increasing the temperature. These results are consistent with a stabilizing stereoelectronic effect on the enzyme adduct caused by N-methylation which hinders free rotation and prevents the sp3-orbital containing the nitrogen nonbonded electrons from being trans to the active site amino acid leaving group.