Optimization of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives as inhibitors of monoamine oxidase

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure-activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole-5,6-dicarbonitrile derivatives (10) exhibit submicromolar IC₅₀ values for the inhibition of MAO, with the most potent MAO-A inhibitor exhibiting an IC₅₀ value of 0.006 μM while the most potent MAO-B inhibitor exhibits an IC₅₀ value of 0.058 μM. Interestingly, an N-oxide derivative ( 4c ) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4-f]indole-5,7-diones (28) also exhibit submicromolar IC₅₀ values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC₅₀ value of 0.011 μM for MAO-A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.     

The monoamine oxidase inhibitors clorgyline and L-deprenyl also affect the uptake of dopamine, noradrenaline and serotonin by rat brain synaptosomal preparations

Clorgyline and l-deprenyl are, respectively, specific type A and type B monoamine oxidase (MAO) inhibitors. We investigated the effects of these two drugs as differential inhibitors of synaptosomal amine uptake and determined how far these effects might be predicted from their properties as specific MAO-A and MAO-B inhibitors. The rank order of inhibition of uptake by clorgyline was found to be: serotonin (ic₅₀ = 10 μM) dopamine (ic₅₀ = 56 μM) noradrenaline (ic₅₀ = 66 μM). The rank order of inhibition of uptake by l-deprenyl was: noradrenaline (ic₅₀ = 26 μM) serotonin (ic₅₀ = 460 μM) dopamine (ic₅₀ = 530 μM). The observation that clorgyline is a more specific inhibitor of the uptake of serotonin (a type A MAO substrate) is consistent with its activity as a type A MAO inhibitor. Paradoxically, L-deprenyl, though a type B MAO inhibitor, is fairly effective at inhibiting the uptake of noradrenaline (a type A MAO substrate).     

Inhibition of brain mitochondrial monoamine oxidases by the endogenous compound 5-hydroxyoxindole

5-Hydroxyoxindole is a recently identified endogenous compound. Its physiological role remains unclear but certain evidence exists, that it may share some regulatory properties with isatin, a known endogenous inhibitor of monoamine oxidase (MAO) type B (MAO-B). In this study several oxidized indoles were tested for their in vitro inhibition of MAO type A (MAO-A) and B of rat brain non-synaptic mitochondria. 5-Hydroxyoxindole was less potent MAO-A inhibitor (IC50 56.8 microM) than isatin (31.8 microM) and especially 5-hydroxyisatin (6.5 microM), but it was the only highly selective MAO-A inhibitor among the all compounds studied (IC50 MAO-A:IC50 MAO-B = 0.044). Thus, the in vitro data suggest that MAO-A may represent potential target for 5-hydroxyoxindole.     

Xanthoangelol and 4-Hydroxyderricin Are the Major Active Principles of the Inhibitory Activities against Monoamine Oxidases on Angelica keiskei K

Monoamine oxidase inhibitors (MAOI) have been widely used as antidepressants. Recently, there has been renewed interest in MAO inhibitors. The activity-guided fractionation of extracts from Angelica keiskei Koidzumi (A. keiskei K.) led to the isolation of two prenylated chalcones, xanthoangelol and 4-hydroxyderricin and a flavonoid, cynaroside. These three isolated compounds are the major active ingredients of A. keiskei K. to inhibit the MAOs and DBH activities. Xanthoangelol is a nonselective MAO inhibitor, and a potent dopamine β-hydroxylase (DBH) inhibitor. IC₅₀ values of xanthoangelol to MAO-A and MAO-B were calculated to be 43.4 μM, and 43.9 μM. These values were very similar to iproniazid, which is a nonselective MAO inhibitor used as a drug against depression. The IC₅₀ values of iproniazid were 37 μM, and 42.5 μM in our parallel examination. Moreover, IC₅₀ value of xanthoangelol to DBH was calculated 0.52 μM. 4-Hydroxyderricin is a potent selective MAO-B inhibitor and also mildly inhibits DBH activity. The IC₅₀ value of 4-hydroxyderricin to MAO-B was calculated to be 3.43 μM and this value was higher than that of deprenyl (0.046 μM) used as a positive control for selective MAO-B inhibitor in our test. Cynaroside is a most potent DBH inhibitor. The IC₅₀ value of cynaroside to DBH was calculated at 0.0410 μM. Results of this study suggest that the two prenylated chalcones, xanthoangelol and 4-hydroxyderricin isolated from A. keiskei K., are expected for potent candidates for development of combined antidepressant drug. A. keiskei K. will be an excellent new bio-functional food material that has the combined antidepressant effect.     

1-methyl substituent and stereochemical effects of 2-phenylcyclopropylamines on the inhibition of rat brain mitochondrial monoamine oxidase A and B

(E)-2-Phenylcyclopropylamine ((E)-TCP), (Z)-2-phenylcyclopropylamine ((Z)-TCP), (E)-1-methyl-2-phenylcyclopropylamine ((E)-MTCP), and (Z)-1-methyl-2-phenylcyclopropylamine ((Z)-MTCP) were synthesized and used to determine to what extent 1-methyl substitution and stereochemistry of 2-phenylcyclopropylamines affect inhibition of monoamine oxidase (MAO). Inhibition of rat brain mitochondrial MAO-A and B by the compounds were measured using serotonin and benzylamine as the substrate, respectively and IC₅₀ values obtained with 95% confidence limits by the method of computation. For the inhibition of MAO-A, (E)-MTCP (IC₅₀=6.2×10^?8M) was found to be 37 times more potent than (Z)-MTCP (IC₅₀=2.3×10^?6 M), whereas the activity of (E)-TCP (IC₅₀=2.9×10^?7 M) was slightly less than that of (Z)-TCP (IC₅₀=2.3×10^?7 M). Similarly, for the inhibition of MAO-B, (E)-MTCP (IC₅₀=6.3×10^?8 M) was 7 times more potent than (Z)-MTCP (IC₅₀=4.7×10^?7 M) and (E)-TCP (IC₅₀=7.8×10^?8 M), 0.6 times as potent as (Z)-TCP (IC₅₀=4.4×10^?8 M). The results suggested that while without 1-methyl group, potency of a (Z)-isomer was comparable to that of (E)-isomer, the methyl group in its (Z)-position was very unfavorable to the inhibition of MAO and that in its (E)-position, the methyl group contributed positively to the potency as found by the fact that (E)-MTCP was 1–5 times more potent than (E)-TCP. In view of the selective inhibition of MAO-A or B, all compounds elicited 4–10 times higher preference for the inhibition of MAO-B over MAO-A and 1-methyl substitution as well as the stereochemical factors did not significantly influence the selectivity.     

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

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

Computer visualisation of the active site of monoamine oxidase-A by means of selective inhibitors

Computer visualisation of the active site of monoamine oxidase (MAO) is based on an assumption that the specific and reversible interaction of a ligand (substrate or inhibitor) with the substrate-binding region of the active site requires shape complementarity. The size of the ligand must allow its accommodation at the substrate-binding region. Analysis of the MAO-inhibitory activity of rigid analogues of isatin and pirlindole revealed a dependence between three-dimensional linear sizes of these molecules and the efficacy of inhibition of both MAO-A and MAO-B. However, flexible molecules did not exhibit any dependence between linear sizes and MAO-B inhibitory potency, possibly because they folded into compact structures could fit into the substrate-binding pocket of MAO-B. 'Moulding' of the substrate/inhibitor binding region by superposition of effective MAO-A inhibitors from various groups of chemicals allowed the shape of substrate/inhibitor binding region to be visualised. 'Removal of contents' from this mould yielded a cavity, which corresponded to the shape of substrate/inhibitor binding region. Such cavity can be used to evaluate the most probable positions known inhibitors take in binding to it. The docking procedure can also be used for searching molecular databases for new inhibitors. Pilot experiments revealed that relatively rigid compounds, which did not fit to this cavity, were poor inhibitors of MAO-A.     

Molecular determinants of MAO selectivity in a series of indolylmethylamine derivatives: biological activities, 3D-QSAR/CoMFA analysis, and computational simulation of ligand recognition

A series of indolylmethylamine derivatives were assayed toward MAO-A and MAO-B inhibition. The K(i) values of these compounds are in the range from 0.8 to >10(6) nM for MAO-A or from 0.75 to 476000 nM for MAO-B. The most selective MAO-A or MAO-B inhibitors elicit a ratio of K(i) in the order of 1500 or 1000, respectively. Comparison of MAO-A and MAO-B CoMFA models showed that both the steric and electrostatic properties at the 5 position of the indole ring are determinant for MAO selectivity. Computational simulations of the complex between this part of the ligand and Phe-208 of MAO-A or Ile-199 of MAO-B, experimentally identified as responsible for substrate selectivity, allowed us to further characterize the nature of these enzyme-inhibitor interactions.     

Enzymic and molecular characteristics of a new form of monoamine oxidase, distinct from form-A and form-B

The present study was undertaken to clarify the enzymic and molecular properties of monoamine oxidase (MAO) in carp brain. In particular, its sensitivities to selective MAO inhibitors, kinetic properties and molecular weight were compared with those of the enzyme in carp liver. The selective and potent MAO-A and MAO-B inhibitors FLA 788(+), FLA 336(+), MD 780236 and benzylcyanide caused dose-dependent inhibitions of MAO activity in both carp brain and liver; the inhibition curves were all single-sigmoidal, and the degrees of inhibition of the activities towards 5-hydroxytryptamine (5-HT, selective MAO-A substrate), tyramine (substrate for both forms of MAO) and beta-phenylethylamine (PEA, selective MAO-B substrate) were similar. This was also the case for inhibition of activity in carp brain by the irreversible and selective MAO-A and MAO-B inhibitors clorgyline and I-deprenyl, indicating the presence in both preparations of a single MAO which differs from either form of MAO. Studies on the substrate specificities and Km values for these three substrates and the inhibitory effects of some compounds suggested that the enzymic characters of MAO in carp preparations were similar and that these enzymes might be FAD-containing enzymes, like MAO in various mammals. By labelling the preparations with radioactive pargyline and then subjecting them to sodium dodecyl sulfate electrophoresis, the apparent molecular weights of carp brain and liver MAO were estimated as 60,000 daltons. The same value was also obtained for rat brain and liver mitochondrial MAO-B. These results indicate that by the present definitions of MAO-A and MAO-B, MAO in carp brain and liver is similar to, but distinct from, both these forms of MAO.     

Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat

The two forms of monoamine oxidase (MAO) in rat intestine and brain homogenates were found to have different K_m and V_max values towards tyramine. The K_m values for the A-form of the enzyme towards this substrate were around 120 μM in both cases, whereas the values for the B-form were about 240 μM. As a consequence, the ratio of activities (MAO-A: MAO-B) towards tyramine are dependent upon the substrate concentration. The MAO-A-selective inhibitors, toloxatone and cimoxatone, were found to be competitive inhibitors of the oxidation of tyramine by the A-form of this enzyme in the rat intestine, with K_i values of 3.4 μM and 3.7 nM respectively. The significance of these results in relation to the “cheese effect”, a pressor response to tyramine after monoamine oxidase inhibition, are discussed.     

β-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)

Peganum harmala L. is a multipurpose medicinal plant increasingly used for psychoactive recreational purposes (Ayahuasca analog). Harmaline, harmine, harmalol, harmol and tetrahydroharmine were identified and quantified as the main β-carboline alkaloids in P. harmala extracts. Seeds and roots contained the highest levels of alkaloids with low levels in stems and leaves, and absence in flowers. Harmine and harmaline accumulated in dry seeds at 4.3% and 5.6% (w/w), respectively, harmalol at 0.6%, and tetrahydroharmine at 0.1% (w/w). Roots contained harmine and harmol with 2.0% and 1.4% (w/w), respectively. Seed extracts were potent reversible and competitive inhibitors of human monoamine oxidase (MAO-A) with an IC₅₀ of 27 μg/l whereas root extracts strongly inhibited MAO-A with an IC₅₀ of 159 μg/l. In contrast, they were poor inhibitors of MAO-B. Inhibition of MAO-A by seed extracts was quantitatively attributed to harmaline and harmine whereas inhibition by root extracts came from harmine with no additional interferences. Stems and leaves extracts were poor inhibitors of MAO. The potent inhibition of MAO-A by seed and root extracts of P. harmala containing β-carbolines should contribute to the psychopharmacological and toxicological effects of this plant and could be the basis for its purported antidepressant actions.     

Monoamine oxidase inhibitory naphthoquinones from the roots ofLithospermum erythrorhizon

Activity-guided fractionation of a hexane-soluble extract of the roots of Lithospermum erythrorhizon, using a mouse brain monoamine oxidase (MAO) inhibition assay, led to the isolation of two known naphthoquinones, acetylshikonin and shikonin, and a furylhydroquinone, shikonofuran E. These compounds were shown to inhibit MAO with IC50 values of 10.0, 13.3, and 59.1 microM, respectively. Although no specificity for MAO-A and MAO-B was shown by acetylshikonin and shikonin, a Lineweaver-Burk plot analysis indicated that the inhibition was competitive for both MAO-A and MAO-B activity.     

Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors

Monoamine oxidase (MAO) enzymes located in human mitochondria oxidize neurotransmitters and bioactivate the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by oxidation to directly-acting neurotoxic pyridinium cations (MPDP⁺/MPP⁺) that produce Parkinsonism. Antioxidants and MAO inhibitors are useful as neuroprotectants. Naturally-occurring substances, antioxidants and redox agents were assessed as inhibitors of the oxidation (bioactivation) of MPTP by human mitochondria and MAO enzymes. Methylene blue, 5-nitroindazole, norharman (β-carboline), 9-methylnorharman (9-methyl-β-carboline) and menadione (vitamin-K analogue) highly inhibited the oxidation of MPTP to the neurotoxic species, MPDP⁺/MPP⁺, in human mitochondria (IC₅₀ of 0.18, 3.1, 9.9, 7.3, and 12.6 μM, respectively). Inhibition by methylene blue was similar to R-deprenyl (IC₅₀ of 0.15 μM), a known neuroprotectant. The naturally-occurring β-carbolines, harmine, harmaline and tetrahydro-β-carboline, and the antioxidants, melatonin, resveratrol, quercetin and catechin showed little or no inhibition. Oxidation of MPTP in mitochondria was performed by human MAO-B and the above active compounds were also inhibitors of this isozyme. Norharman and 5-nitroindazole were competitive inhibitors of MAO-B whereas methylene blue inhibited MPTP oxidation (IC₅₀ of 50 nM) under a mixed type and predominantly uncompetitive mechanism. Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species.     

Substituted Xanthones as Selective and Reversible Monoamine Oxidase A (MAO-A) Inhibitors

l,3-Dihydroxy-2-methylxanthone (XI), its 4-chloro and 4-bromo derivatives (X1-C1 and Xl-Br), and 1 ,3-dihydroxy-4-methylxanthone were investigated for their inhibition activities toward MAO. A hyperbolic function was derived to fit the data and to calculate IC₅₀ values. The compounds proved to be reversible and selective inhibitors of MAO-A, with XI displaying the highest activity (IC₅₀ = 3.7 µM).     

Inhibition of rat brain monoamine oxidase enzymes by fluoxetine and norfluoxetine

Fluoxetine and its primary metabolite, norfluoxetine, are inhibitors of neuronal uptake of 5-hydroxytryptamine. While fluoxetine has also been reported to inhibit monoamine oxidase (MAO) in vitro at concentrations much lower than those measured in brain following chronic fluoxetine treatment, neurochemical profiles are not consistent with substantial MAO inhibition in vivo. In an attempt to explain this inconsistency, we have examined the interactions of fluoxetine and norfluoxetine with rat brain MAO-A and -B by a radiochemical assay method.Fluoxetine and norfluoxetine were competitive inhibitors of MAO-A in vitro, with K_i values of 76.3 M and 90.5 M, respectively. Both compounds were non competitive or uncompetitive inhibitors of MAO-B in vitro. Inhibition of MAO-B was time-dependent and was very slowly reversible by dialysis. IC₅₀ values versus metabolism of 50 M, -phenylethylamine were 17.8 M (fluoxetine) and 18.5 M (norfluoxetine). Analysis of the time-dependence of MAO-B inhibition by fluoxetine revealed that an initial competitive interaction between the enzyme and the inhibitor (K_i 245 M) was followed by tight-binding enzyme inactivation (k_inact 0.071 min^–1).Following administration of fluoxetine (20 mg kg^–1 day^–1]) for 7 days, the cortical concentration of fluoxetine + norfluoxetine was estimated by gas-liquid chromatography to be 700 M. Such drug treatment reduced MAO-A activity by 23% in 1:8 (w/v) cortical homogenates, but not in 1:80 homogenates. Inhibition of MAO-B in 1:8 homogenates was modest (12%) and was not significantly reduced by homogenate dilution. The concentration of 5-hydroxyindole-3-acetic acid, measured by high pressure liquid chromatography, was reduced by 47% in cortices from drug-treated rats, while concentrations of 5-hydroxytryptamine, noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were unchanged. These results suggest that, following chronic drug administration leading to relatively high tissue concentrations of fluoxetine and norfluoxetine, inhibition of either form of MAO would be restricted by competition for the enzyme with intraneuronal amine substrates.     

Relevance of benzyloxy group in 2-indolyl methylamines in the selective MAO-B inhibition

1. Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition. 2. A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy-indolyl methylamines, N-(2-propynyl)-2-(5-benzyloxyindol)methylamine FA-73 was the most potent MAO-B 'suicide' inhibitor studied. 3. The Ki values for MAO-A and MAO-B were 800+/-60 and 0.75+/-0.15 nM, respectively. These data represent a selectivity value of 1066 for MAO-B, being 48 times more selective than L-deprenyl (Ki values of 376+/-0.032 and 16.8+/-0.1 nM for MAO A and MAO-B, respectively). The IC50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150+/-8 microM for FA-73 and 68 +/- 10 microM for L-deprenyl whereas in human caudate tissue the IC50 values were 0.36+/-0.015 microM for FA-73 and 0.10+/-0.007 microM for L-deprenyl. Moreover, mouse brain MAO-B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg(-1) administration, MAO-A activity was not affected. 4. These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non-amphetamine-like MAO-B inhibitors with therapeutic potential for the treatment of neurological disorders.     

Monoamine oxidase inhibitory components from the roots ofSophora flavescens

In our search for monoamine oxidase (MAO) inhibitors from natural resources, we found that the methanol extract of the roots of Sophora flavescens showed an inhibitory effect on mouse brain monoamine oxidase (MAO). Bioactivity-guided isolation of the extract yielded two known flavonoids, formononetin (1) and kushenol F (2), as active compounds along with three inactive compounds, oxymatrine (3), trifolirhizin (4), and beta-sitosterol (5). Formononetin (1) and kushenol F (2) showed significant inhibitory effects on MAO in a dose-dependent manner with IC50 values of 13.2 and 69.9 microM, respectively. Formononetin (1) showed a slightly more potent inhibitory effect against MAO-B (IC50: 11.0 microM) than MAO-A (IC50: 21.2 microM). Kushenol F (2) also preferentially inhibited the MAO-B activity than MAO-A activity with the IC50 values of 63.1 and 103.7 microM, respectively.     

Monoamine oxidase inhibition by selected dye compounds

Monoamine oxidase (MAO) is an important drug target as the MAO isoforms play key roles in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as in neuropsychiatric diseases such as depression. Methylene blue is an inhibitor of MAO‐A, while azure B, the major metabolite of methylene blue, and various other structural analogues retain the ability to inhibit MAO‐A. Based on this, the present study evaluated 22 dyes, many of which are structurally related to methylene blue, as potential inhibitors of human MAO‐A and MAO‐B. The results highlighted three dye compounds as good potency competitive and reversible MAO inhibitors, and which exhibit higher MAO inhibition than methylene blue: acridine orange, oxazine 170 and Darrow red. Acridine orange was found to be a MAO‐A specific inhibitor (IC₅₀ = 0.017 μM), whereas oxazine 170 is a MAO‐B specific inhibitor (IC₅₀ = 0.0065 μM). Darrow red was found to be a non‐specific MAO inhibitor (MAO‐A, IC₅₀ = 0.059 μM; MAO‐B, IC₅₀ = 0.065 μM). These compounds may be advanced for further testing and preclinical development, or be used as possible lead compounds for the future design of MAO inhibitors.     

In vitro effects of acetylcholinesterase reactivators on monoamine oxidase activity

Administration of acetylcholinesterase (AChE) reactivators (oximes) is usually used in order to counteract the poisoning effects of nerve agents. The possibility was suggested that oximes may show some therapeutic and/or adverse effects through their action in central nervous system. There are no sufficient data about interaction of oximes with monoaminergic neurotransmitter's systems in the brain. Oxime-type AChE reactivators pralidoxime, obidoxime, trimedoxime, methoxime and HI-6 were tested for their potential to affect the activity of monoamine oxidase of type A (MAO-A) and type B (MAO-B) in crude mitochondrial fraction of pig brains. The compounds were found to inhibit fully MAO-A with half maximal inhibitory concentration (IC₅₀) of 0.375 mmol/l (pralidoxime), 1.53 mmol/l (HI-6), 2.31 mmol/l (methoxime), 2.42 mmol/l (obidoxime) and 4.98 mmol/l (trimedoxime). Activity of MAO-B was fully inhibited by HI-6 and pralidoxime only with IC₅₀ 4.81 mmol/l and 11.01 mmol/l, respectively. Methoxime, obidoxime and trimedoxime displayed non-monotonic concentration dependent effect on MAO-B activity. Because oximes concentrations effective for MAO inhibition could not be achieved in vivo at the cerebral level, we suppose that oximes investigated do not interfere with brain MAO at therapeutically relevant concentrations.