Monoamine oxidase inhibition by isocarboxazid.
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Humans↗
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Synthesis of substituted anilino-3-methoxy-4-substituted acetoxy) benzylidenes and their monoamine oxidase inhibitory and anticonvulsant properties.
Several substituted anilino-(3-methoxy-4-substituted acetoxy) benzylidenes were synthesized and characterized by their sharp melting points and elemental analyses. All substituted benzylidenes competitively inhibited the in vitro monoamine oxidase activity of rat brain homogenates and possessed anticonvulsant activity against pentylenetetrazol-induced convulsions in mice.
Animals↗
Parents of high risk subjects defined by levels of monoamine oxidase activity.
Thirty-seven parents of probands with low platelet monoamine oxidase (MAO) activity levels and 38 parents of high MAO probands were examined for MAO activity, past and present psychopathology, and reported psychopathology in other relatives. Results showed generally positive and significant correlations between parents' and children's MAO levels, significantly greater rates of "high MAO related" disorders in parents and relatives of high MAO probands and of "low MAO related" disorders and symptoms in parents and relatives of low MAO probands. Support for a two-directional monoamine hypothesis of affective disorders is suggested.
Alcoholism↗
Analysis of conserved active site residues in monoamine oxidase A and B and their three-dimensional molecular modeling.
Monoamine oxidase (MAO) is a key enzyme responsible for the degradation of serotonin, norepinephrine, dopamine, and phenylethylamine. It is an outer membrane mitochondrial enzyme existing in two isoforms, A and B. We have recently generated 14 site-directed mutants of human MAO A and B, and we found that four key amino acids, Lys-305, Trp-397, Tyr-407, and Tyr-444, in MAO A and their corresponding amino acids in MAO B, Lys-296, Trp-388, Tyr-398, and Tyr-435, play important roles in MAO catalytic activity. Based on the polyamine oxidase three-dimensional crystal structure, it is suggested that Lys-305, Trp-397, and Tyr-407 in MAO A and Lys-296, Trp-388, and Tyr-398 in MAO B may be involved in the non-covalent binding to FAD. Tyr-407 and Tyr-444 in MAO A (Tyr-398 and Tyr-435 in MAO B) may form an aromatic sandwich that stabilizes the substrate binding. Asp-132 in MAO A (Asp-123 in MAO B) located at the entrance of the U-shaped substrate-binding site has no effect on MAO A nor MAO B catalytic activity. The similar impact of analogous mutants in MAO A and MAO B suggests that these amino acids have the same function in both isoenzymes. Three-dimensional modeling of MAO A and B using polyamine oxidase as template suggests that the overall tertiary structure and the active sites of MAO A and B may be similar.
Amino Acid Sequence↗
Type A and type B monoamine oxidase activities in rat brain and liver mitochondria: a comparison of their properties using the non-ionic detergent Triton X-100.
1. The effects of the non-ionic detergent Triton X-100 on the heterogeneity of monoamine oxidase activities were studied and compared in synaptic (fractions SM and SM2) and non-synaptic (fraction M) brain mitochondria and liver mitochondria. 2. Triton X-100 inhibited type A and type B monoamine oxidase activities in all four mitochondrial fractions in a concentration-dependent manner. Liver mitochondrial enzymatic activities were much more sensitive to this inhibition than those of brain mitochondria. The activities in the SM fraction of synaptic brain mitochondria were the least susceptible. 3. In all four mitochondrial fractions, type A activities were more sensitive to inhibition than type B activities. 4. These results suggest that the membrane micro-environment around the enzyme molecules in situ may be important in the functional expression of the activity of the enzyme.
Animals↗
Effect of amphetamine on brain catecholamines, brain beta-endorphin, serum prolactin, catechol-O-methyltransferase and monoamine oxidase of various organs in the rat.
Rats were treated with amphetamine to induce an amphetamine psychosis which resembles paranoid schizophrenia. Brain catecholamines, brain beta-endorphin, serum prolactin as well as catechol-O-methyltransferase and monoamine oxidase were subsequently measured. The norepinephrine levels were significantly lower in brain regions of rats treated with amphetamine whereas levels of dopamine and beta-endorphin remained the same. No significant changes were found in the levels of catechol-O-methyltransferase, monoamine oxidase and serum prolactin. In view of recent findings by other investigators in this field, our results suggest an important role of the adrenergic system in the pathogenesis of amphetamine psychosis.
Amphetamine↗
The influence of some compounds commonly used in biochemical studies of mitochondria on the activity of monoamine oxidases.
It was previously described that low concentrations of sodium azide monoamine oxidase (MAO) B assayed by spectrophotometric measurement of benzaldehyde or by hydrogen peroxide accumulation. We failed to confirm this effect using radiometric determination of MAO activity. Tris or dinitrophenol inhibit MAO. The data suggest that some "regulatory effects" depend on the assay of MAO activity.
2,4-Dinitrophenol↗
Ring-substituted analogues of tranylcypromine as monoamine oxidase inhibitors.
4-Fluorotranylcypromine and 4-methoxytranylcypromine, in which the 4-position of the phenyl ring is protected from metabolic ring hydroxylation, were tested for their ability to inhibit, relative to tranylcypromine, monoamine oxidase (MAO) -A and -B in rat brain after administration of low doses (1.2 and 3.7 mumol/kg) of the drugs. One hour after intraperitoneal injection of the lower dose, tranylcypromine was weaker than 4-fluorotranylcypromine and 4-methoxytranylcypromine at inhibiting MAO-A. After long-term (28 day) administration of a dose of 3.7 mumol/kg/day (administered via osmotic minipumps), 4-fluorotranylcypromine had a slightly stronger inhibitory effect on MAO-B than did the other two drugs. At the same time and dose both 4-substituted analogues were slightly more potent inhibitors of MAO-A than was tranylcypromine. After 28 days of administration at a daily dose of 1.2 mumol/kg/day, both analogues produced greater inhibition of MAO-A and -B than did tranylcypromine. 4-Methoxytranylcypromine and 4-fluorotranylcypromine were similar in their extent of inhibition of MAO-B but the former was more potent than the latter at inhibition MAO-A.
Animals↗
Contribution of monoamine oxidase (MAO) to the binding of tertiary basic drugs in lung mitochondria.
The effects of tertiary amine-containing basic drugs on the enzymes located in the mitochondria and the effect of monoamine oxidase inhibitors (MAOIs) on drug accumulation in lung mitochondria have been studied. Various basic drugs inhibited MAO activity but not other mitochondrial marker enzymes. The potency of MAO inhibition correlated well with their lipid solubility, and the basic drugs inhibited MAO activity dose dependently and competitively. Further, MAO inhibition correlated well with binding affinity to lung mitochondria, and the binding of tertiary amine drugs to lung mitochondria was decreased by treatment with MAOIs. A good correlation was observed between the potency of MAOIs to inhibit the binding of the basic drug to the high-affinity site in mitochondria and the MAO inhibitory activity in mitochondria. These results indicate that mitochondrial MAO is one of the binding sites for tertiary basic drugs in the lung. We think that the action and/or adverse reaction of some drugs may result from inhibition of mitochondrial MAO to metabolize various biogenic amines and that mitochondrial MAO may function as a reservoir for basic drugs.
Animals↗
Commonly used L-amino acid decarboxylase inhibitors block monoamine oxidase activity in the rat.
The effects of the peripheral aromatic amino acid decarboxylase (AADC) inhibitors, carbidopa and benserazide, and the central AADC inhibitor, 3-hydroxybenzylhydrazine (NSD-1015) on peripheral and brain monoamine oxidase (MAO) A and B activity were investigated in the rat. In vitro, carbidopa, benserazide and NSD-1015 all potently inhibited hepatic MAO A and B activity (IC(50) 10-50 micro M). In ex vivo studies following systemic drug administration, NSD-1015 (100 mg/kg ip) produced 88% and 96% inhibition of hepatic and striatal MAO A and B activity respectively. Carbidopa (12.5 mg/kg i.p.) and benserazide (50 mg/kg i.p.) had no effect on striatal MAO A activity or hepatic MAO B activity. However, they inhibited striatal MAO B activity by 45 +/- 10% and 36 +/- 10% respectively. In conclusion, carbidopa and benserazide may not only protect L-DOPA from peripheral decarboxylation, but also increase striatal dopamine content through MAO inhibition. NSD-1015 should not be used to investigate the neuromodulatory role of L-DOPA as it potently inhibits rat striatal MAO.
Animals↗
Nitric oxide inhibits mitochondrial monoamine oxidase activity and decreases outer mitochondria membrane fluidity.
The recent finding that mitochondria contain a nitric oxide (NO) synthase suggests that this compound is involved in the regulation of various mitochondrial functions. Monoamine oxidase (MAO) is embedded in the outer mitochondrial membrane. NO modulates membrane fluidity. Thus, the aim of the present work was to study the effect of NO on mitochondrial MAO activity and membrane fluidity. An outer mitochondrial membrane fraction (OMMF) was obtained from rat liver. OMMF was incubated with various concentrations of S-nitroso-N-acetylpenicillamine (SNAP), a NO donor. MAO activity and fluidity were measured by a spectrophotometric assay and by the polarization of fluorescence technique, respectively. It was found that small concentrations of SNAP (0.4-40 microM) were capable of inhibiting MAO activity but unable to decrease fluidity significantly. In contrast, larger amounts of SNAP (40-300 microM) effectively decreased membrane fluidity, but were not able to further decrease MAO activity. This information suggests that mitochondrial MAO and membrane fluidity possess different sensitivity to the effect of NO. Unfortunately, the mechanism by which NO inhibits MAO remains unknown at present. However, it seems likely that the effect of NO on MAO activity is by a direct interaction of the compound or a metabolite to the protein.
Animals↗
[Monoamine oxidase activity and noradrenaline concentration in tissue from symmetrical areas of cerebral cortex].
Tissue of the human brain cortex was obtained for investigations in neurosurgical operations and in autopsy. Homogenates of the tissue of symmetrical visual, auditory and skin areas were similar in the monoamine oxidase activity and adrenalin content whereas homogenates of the motor cortex tissue differed from each other in these parameters. Samples of tissue of the written language center were asymmetrical in their monoamine oxidase activity.
Adult↗
N-(6-18F-fluorohexyl)-N-methylpropargylamine: a fluorine-18-labeled monoamine oxidase B inhibitor for potential use in PET studies.
We have synthesized N-(6-18F-fluorohexyl)-N-methylpropargylamine (18F-FHMP) as a positron emission tomography (PET) radiotracer for monoamine oxidase B (MAO-B). The radiosynthesis was carried out by a fluorine-for-bromine substitution in 30-40% radiochemical yield in specific activities of 1-2 Ci/micromol. Selectivity for MAO-B was demonstrated by the high affinity of (R)-deprenyl (IC50 = 6.8 nM) and lower affinity of clorgyline (IC50 = 1.2 microM) for the inhibition of 18F-FHMP binding in vitro in rat brain homogenates. In vitro autoradiographic studies in rat brain slices showed localization of 18F-FHMP in regions such as the ependyma of the lateral ventricle, dorsal raphe, area postrema, and other regions such as the cerebellum. The specific binding observed in the autoradiograms was displaced by preincubation with (R)-deprenyl. In in vivo experiments, the uptake of 18F-FHMP in the rat brains was high (0.10-0.20% injected dose/g). The binding of 18F-FHMP in the rat brain correlated with the general distribution of MAO-B and was displaced completely by preadministration of 10 microM (R)-deprenyl. These results suggest that 18F-FHMP is a potential PET radiotracer for MAO-B for use in in vitro and in vivo experiments.
Animals↗
Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs.
Genetic loss or pharmacological inhibition of monoamine oxidase A (MAOA) in mice leads to a large increase in whole-brain levels of serotonin (5-HT). Excess 5-HT in mouse neonates prevents the normal barrel-like clustering of thalamic axons in the somatosensory cortex. Projection fields of other neuron populations may develop abnormally. In the present study, we have analyzed the localization of 5-HT immunolabeling in the developing brain of MAOA knock-out mice. We show numerous atypical locations of 5-HT during embryonic and postnatal development. Catecholaminergic cells of the substantia nigra, ventral tegmental area, hypothalamus, and locus ceruleus display transient 5-HT immunoreactivity. Pharmacological treatments inhibiting specific monoamine plasma membrane transporters and genetic crosses with mice lacking the dopamine plasma membrane transporter show that the accumulation of 5-HT in these catecholaminergic cells is attributable to 5-HT uptake via the dopamine or the norepinephrine plasma membrane transporter. In the telencephalon, transient 5-HT immunolabeling is observed in neurons in the CA1 and CA3 fields of the hippocampus, the central amygdala, the indusium griseum, and the deep layers of the anterior cingulate and retrosplenial cortices. In the diencephalon, primary sensory nuclei, as well as the mediodorsal, centrolateral, oval paracentral, submedial, posterior, and lateral posterior thalamic nuclei, are transiently 5-HT immunolabeled. The cortical projections of these thalamic nuclei are also labeled. In the brainstem, neurons in the lateral superior olivary nucleus and the anteroventral cochlear nucleus are transiently 5-HT immunolabeled. None of these structures appear to express the monoamine biosynthetic enzyme L-aromatic amino acid decarboxylase. The administration of monoamine plasma membrane transporter inhibitors indicates that the 5-HT immunolabeling in these structures is attributable to an uptake of 5-HT by the 5-HT plasma membrane transporter. This points to neuron populations that form highly precise projection maps that could be affected by 5-HT during specific developmental stages.
Animals↗
4-(Aminomethyl)-1-aryl-2-pyrrolidinones, a new class of monoamine oxidase B inactivators.
Both 4-(aminomethyl)-1-phenyl-2-pyrrolidinone (4a) and 4-(aminomethyl)-1- (methoxyphenyl)-2-pyrrolidinone (4b) hydrochlorides were synthesized via a six-step sequence, which represents a general approach to 1,4-disubstituted 2-pyrrolidinones. Both of these compounds inactivated monoamine oxidase B and represent the first in a new class of monomamine oxidase inactivators.
Animals↗
Imidazoline-binding domains on monoamine oxidase B and subpopulations of enzyme.
A series of phenoxy-substituted methylimidazoline derivatives were synthesized and used to define the ligand recognition properties of the imidazoline-binding domain (IBD) on monoamine oxidase (MAO)-B and its role in substrate processing. The rank order of potency for selected compounds in competitive binding studies with the imidazoline [(3)H]idazoxan was different from that in enzyme activity assays, suggesting that the IBD and the site involved in enzyme inhibition are distinct. IC(50) values for inhibition of MAO-B activity by imidazoline/guanidinium ligands were one to two orders of magnitude greater than ligand concentrations that probably saturate the IBD, but were equal to the K(d) values of these ligands in competitive binding assays with the reversible MAO-B inhibitor [(3)H]Ro 19-6327. In addition, the degree of enzyme inhibition by these ligands was similar in platelet and liver, tissues exhibiting 10-fold differences in the amount of the IBD-accessible enzyme subpopulation. These data suggested that the inhibitory effect of these compounds on MAO-B activity involved a secondary interaction with the enzyme domain recognizing the inhibitor Ro 19-6327 and does not involve interaction with the IBD. Subsequent radioligand-binding studies indicated that human liver MAO-B actually existed as two distinct populations that differed in the accessibility of their IBD. The relatively small amounts of MAO-B possessing an accessible IBD ( approximately 5% in human liver) precludes determination of the functional consequences of ligand binding to the IBD. This subpopulation of MAO-B may be selectively regulated or generated in different individuals or tissues and targeted by pharmacologically active compounds in a cell type-specific manner.
Binding Sites↗
Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury.
BACKGROUND: Serotonin (5-hydroxytryptamine [5-HT]), released by activated platelets during cardiac ischemia, is metabolized by the mitochondrial enzyme monoamine oxidase A (MAO-A). Because hydrogen peroxide is one of the byproducts of 5-HT degradation by MAO-A, we investigated the potential role of reactive oxygen species generated by MAOs in 5-HT-dependent cardiomyocyte death and post-ischemia-reperfusion cardiac damage. METHODS AND RESULTS: Treatment of isolated adult rat cardiomyocytes with 5-HT induced intracellular oxidative stress and cell apoptosis. The apoptotic cascade triggered by 5-HT involves release of cytochrome c, upregulation of proapoptotic Bax protein, and downregulation of antiapoptotic Bcl-2 protein. These effects were prevented by inhibition of amine transporter or MAO, antioxidants, or iron chelation. In contrast, cardiomyocyte apoptosis was only slightly affected by the 5-HT(2B) receptor antagonist SB 206553. In vivo, inhibition of MAO-A largely reduced myocardial ultrastructural damage induced by 30 minutes of ischemia followed by 60 minutes of reperfusion in the rat heart. Cardioprotective effects of MAO inhibitors were associated with the prevention of postischemic oxidative stress, neutrophil accumulation, and mitochondrial-dependent cell death and were not reverted by SB 206553. Administration of MAO-A inhibitors during ischemia was still effective in preventing cardiac damage. CONCLUSIONS: Our results supply the first direct evidence that oxidative stress induced by MAO is responsible for receptor-independent apoptotic effects of 5-HT in cardiomyocytes and postischemic myocardial injury. These findings provide new insight into the mechanisms of 5-HT action in the heart and may constitute the basis for novel therapies.
Animals↗
Mechanism-based inactivation of mitochondrial monoamine oxidase by N-(1-methylcyclopropyl)benzylamine.
Three different radioactively labeled N-(1-methylcyclopropyl)benzylamines [N-(1-Me)CBA] were synthesized and used to show which atoms of the inactivator remain bound to monoamine oxidase (MAO) after inactivation. Organic chemical reactions were employed to elucidate the structure of the enzyme adduct and clarify the mechanism of inactivation. Following inactivation and dialysis, the benzyl substituent is lost, but the methyl group and cyclopropyl carbons remain attached to the enzyme even after further dialysis against solutions containing 1 mM benzylamine or 8 M urea. Treatment of inactivated enzyme with sodium cyanoborohydride prior to dialysis results in the retention of the benzyl group, suggesting an imine linkage. One hydride from sodium boro[3H]hydride is incorporated into the dialyzed inactivated enzyme consistent with a ketone functional group. When Pronase-digested N-(1-Me)CBA-inactivated MAO is treated with basic potassium triiodide, iodoform is isolated, indicating the presence of a methyl ketone. During inactivation, the optical spectrum of the covalently bound active site flavin changes from that of oxidized to reduced flavin. After urea denaturation, the flavin remains reduced, suggesting covalent linkage of the inactivator to the cofactor. On the basis of previous results [Silverman, R. B., Hoffman, S. J., & Catus, W. B., III (1980) J. Am. Chem. Soc. 102, 7126-7128], it is proposed that the mechanism of inactivation involves transfer of one electron from N-(1-Me)CBA to the flavin, resulting in an amine radical cation and a flavin radical. Then, either the cyclopropyl ring is attacked by the flavin radical or the cyclopropyl ring opens, and the radical generated is captured by the flavin radical. The product of this mechanism is the imine of benzylamine and 4-flavinyl-2-butanone, the proposed enzyme-inactivator adduct.
Amines↗