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PubMed1976

Synthesis of substituted thiobenzoxazoles/benzothiazoles: inhibition of cellular respiratory and monoamine oxidase activities and anticonvulsant property.

Several 2-(substituted alkoxy/hydrazinocarbonyl acetanilidothio)benzoxazoles/benzothiazoles were synthesized and characterized by their sharp melting points, elemental analyses, and IR spectra. All thiobenzoxazoles/benzothiazoles possessed low anticonvulsant activity, which was reflected by the 10-40% protection afforded by these compounds against pentylenetetrazol-induced convulsions. All thiobenzoxazoles/benzothiazoles inhibited selectively the nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, DL-isocitrate, and alpha-ketoglutarate by rat brain homogenates. NAD-independent oxidation of succinate remained unaltered. All 2-(substituted hydrazinocarbonyl acetanilidothio)benzoxazoles/benzothiazoles inhibited monoamine oxidase activity of rat brain homogenates. Greater monoamine oxidase inhibition was observed with thiobenzothiazoles than with the corresponding thiobenzoxazoles/benzothiazoles was found to be unrelated with their ability to inhibit cellular respiratory and monoamine oxidase activities of rat brain homogenates.

Animals↗
PubMed1976

Evidence for a single catalytic binding site on human brain type B monoamine oxidase.

The tricyclic antidepressant drug, amitriptyline, inhibited the B form of human brain mitochondrial monoamine oxidase (MAO) under normal atmospheric conditions in a noncompetitive manner when phenylethylamine (PEA) was used as substrate and competitively when benzylamine (BzNH2) was employed as substrate. In addition, it was also found that PEA and BzNH2 inhibited each other's degradation noncompetitively. Similar results have previously been reported with human platelet MAO. These data suggest that the catalytic binding sites for PEA and BzNH2 on the B form of human brain MAO may be different. Attempts were made to further distinguish these catalytic binding sites on the brain oxidase using the irreversible MAO inhibitors, pargyline and clorgyline. Though these drugs have considerably different affinities for the B form of the oxidase, the degree to which either compound inhibited PEA or BzNH2 deamination was essentially identical. When incubations were performed at elevated oxygen concentrations PEA and BzNH2 became mutually competitive inhibitors of each other's metabolism. Also at the higher levels of oxygen, amitriptyline inhibition of PEA deamination approached a competitive fashion. These results suggest that PEA and BzNH2 share a common catalytic binding site on the B form of MAO and, in addition, bind to an inhibitory site on the reduced form of the oxidase. Accordingly, the data indicate that amitriptyline also binds to both the oxidized and reduced forms of this human brain oxidase.

Benzylamines↗
PubMed1983

Mechanism of the involvement of monoamine oxidase in the regulation of (Na+ + K+)-ATPase in rat brain.

Increasing concentrations of dopamine fail to give a biphasic response to (Na+ + K+)-ATPase activity in various subcellular fractions of rat brain preincubated with monoamine oxidase inhibitors, viz. 1 X 10(-4) M clorgyline and 1 X 10(-4) M deprenyl. The product of the monoamine-oxidase-catalysed reaction with dopamine as substrate is 3-methoxy-4-hydroxyphenylacetaldehyde. An analogue of this product is 3-methoxy-4-hydroxybenzaldehyde. This analogue, when incubated with the subcellular fractions which had been preincubated with monoamine oxidase inhibitors and dopamine, gave a more pronounced biphasic response to (Na+ + K+)-ATPase activity than that observed in the fractions incubated with dopamine alone.

Animals↗
PubMed1975

Synthesis of 2-(4-arylthiosemicarbazidocarbonylthio)benzthiazoles and their monoamine oxidase inhibitory and anticonvulsant properties.

Ten 2-(4-arylthiosemicarbazidocarbonylthio)benzthiazoles were synthesized, characterized, and evaluated for their monoamine oxidase inhibitory and anticonvulsant activities. All substituted benzthiazoles inhibited activity of monoamine oxidase in rat brain homogenate where the degree of enzyme inhibition was higher with kynuramine as compared to tyramine and 5-hydroxytryptamine as the substrates. All substituted benzthiazoles possessed measurable anticonvulsant activity against pentylenetetrazol-induced convulsions.

Animals↗
PubMed1975

[Monoamine oxidase (XXXVI). Characteristics of benzylamine oxidase in the dog serum].

Enzymic properties of monoamine oxidase (MAO) in dog serum were studied and the following results were obtained. Some of enzymic properties of MAO in dog serum differed from that of mitochondrial MAO. When dog serum was fractionated by ammonium sulfate, proteins were concentrated in two fractions, such as 25 approximately 33% and 67 approximately 80% of saturated ammonium sulfate fraction, while MAO activity was concentrated in 40 approximately 50% of saturated ammonium sulfate fraction. The reaction rate of MAO in dog serum was found to be proportional to enzyme concentration. The optimum pH of MAO in dog serum was 7.0 which differed from that of MAO in rabbit serum (pH 8.0). Tris-HCl buffer strongly inhibited MAO activity in dog serum. When benzylamine was used as substrate, the highest activity was obtained compared with the other substrate used. The activities with butylamine, amylamine, beta-phenylethylamine and tyramine showed about 30% while tryptamine and serotonin showed 3 approximately 10% compared to that with benzymlamine as substrate. The value of pI50 of catron was about 3 X 10(-6) M and that of harmaline was about 3 X 10(-5) M, but pargyline did not inhibit MAO activity in dog serum at the concentration of 1 X 10(-4) M.

Ammonium Sulfate↗
PubMedDate not supplied

Effects of selective inhibition of type A and type B monoamine oxidase on intraocular pressure in the cat and the rabbit.

Ocular tension of conscious cats and rabbits was measured after topical application of clorgyline, a selective inhibitor of type A monoamine oxidase, or deprenyl, a selective inhibitor of line (1,4 and 12%) showed a dose-related reduction of intraocular pressure, with maximal lowerings amounting to 6 to 7 mm Hg. Pretreatment of eyes with clorgyline, 1%, markedly potentiated the pressure lowering response to epinephrine, 0.1%, applied topically. Sympathetic denervation almost completely abolished the effect of clorgyline. In contrast, deprenyl (2 to 8%) did not lower intraocular pressure after topical application to cat or rabbit eyes. beta-Phenylethylamine (2 to 16%) a specific substrate for the B form of monoamine oxidase, likewise did not lower ocular tension when given either alone or after pretreatment with deprenyl. These findings suggest that the intraocular pressure lowering effect of monoamine oxidase inhibitors is due primarily to inhibition of the A form of the enzyme and is dependent on intact sympathetic innervation.

Administration, Topical↗
PubMedDate not supplied

[Effect of oxidized indoles on monoamine oxidase activity in the rat brain mitochondria].

There is increasing evidence, that oxidized indoles, isatin, 5-hydroxyoxindole, 2-oxindole, play important regulatory functions in the brain. Isatin and 5-hydroxyoxindole share some common regulatory properties in cell cultures (Cane et al., 2000, BBRC, 276, 379), however, their effects on brain mitochondrial monoamine oxidases, a potential target for their action, have not been compared yet. Isatin acted as a rather selective monoamine oxidase B inhibitor, whereas 5-hydroxyoxindole was more selective monoamine oxidase A inhibitor, but it was less potent than that of 5-hydroxyisatin, a synthetic analogue of isatin.

Animals↗
PubMed2000

Selective monoamine oxidase subtype inhibition and striatal extracellular dopamine in the guinea-pig.

Striatal microdialysate levels of dopamine (DA) in conscious guinea-pigs were measured following acute (1 day) and chronic (21 days) treatment with deprenyl (2 and 0.25 mg kg(-1) s.c., respectively) or clorgyline (4 and 1 mg kg(-1) s.c., respectively), as well as by combination treatment using the same doses of the two inhibitors. These treatments caused selective inhibition of monoamine oxidase type B (MAO-B) or monoamine oxidase type A (MAO-A) respectively. Neither acute nor chronic treatments with deprenyl or clorgyline increased basal or KCl-induced DA levels. Acute and chronic clorgyline treatments were accompanied by significant reductions in striatal microdialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). On the other hand, both acute and chronic deprenyl treatments were accompanied by significant increases in microdialysate HVA with no effect on DOPAC levels. Acute or chronic combined treatment with clorgyline and deprenyl increased tissue but not microdialysate DA levels. The combination treatment given chronically also reduced KCl-induced DA release but enhanced amphetamine-induced DA release. Microdialysate DA levels increased to a smaller extent in guinea-pig than in rat following local striatal infusion of GBR-12909 (100 microM). The difference between guinea-pigs and rats in the response to GBR-12909, could be the result of a lower dopaminergic innervation and/or density of DA transporter. This difference may explain why striatal microdialysate DA levels increased following chronic deprenyl treatment in the rat but not in the guinea-pig.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

[3H]-idazoxan binding to rabbit cerebral cortex recognises multiple imidazoline I2-type receptors: pharmacological characterization and relationship to monoamine oxidase.

1. In rabbit cerebral cortical homogenates, saturation analysis of [3H]-idazoxan, an alpha 2-adrenoceptor antagonist, revealed high affinity binding to a single site with high density. Competition experiments demonstrated that the [3H]-idazoxan recognition site was insensitive to the catecholamines, adrenaline and noradrenaline and possessed a low affinity for the alpha 2- and alpha 1-adrenoceptor antagonists, rauwolscine, yohimbine and prazosin, suggesting that the site was not an adrenoceptor. Mapping [3H]-idazoxan binding sites in the forebrain of rabbits by autoradiography, showed high densities of I2 sites in the medial preoptic area and in the stria terminalis. Moderate binding was found in caudate nucleus, putamen, cerebral cortex and hippocampus. 2. The imidazolines cirazoline, naphazoline, guanabenz and BRL44408 along with amiloride, which is structurally related to the imidazolines, all had high affinity for the [3H]-idazoxan site, suggesting that the site was related to the I2 imidazoline-recognition site described by other groups. However, the imidazolines, clonidine and UK-14,304 and the structurally related rilmenidine all had a low affinity for the binding site, showing that [3H]-idazoxan was not binding to the I1 imidazoline-recognition site found in rat, bovine and human medulla oblongata. 3. Naphazoline, guanabenz, clonidine and amiloride competition studies had Hill slopes which were significantly different from unity (P < 0.01) and computer analysis showed that the [3H]-idazoxan binding data could be best fitted to a model which considers binding to two sites (P < 0.01). One site has a high affinity for idazoxan, cirazoline, naphazoline, guanabenz and amiloride and a moderate affinity for BRL44408 and clonidine (70% of binding) and the second site (30% of binding) has a high affinity for idazoxan and cirazoline, but a lower affinity for naphazoline, guanabenz, amiloride,BRL44408 and clonidine.4. Experiments using [3H]-RX821002, in contrast to [3H]-idazoxan, clearly demonstrated the presence ofa single type of alpha2-adrenoceptor in rabbit cortex with a pharmacological profile which is similar to the alpha2A-adrenoceptor possessing a high affinity for yohimbine, rauwolscine, BRL44408 and oxymetazoline,but a lower affinity for prazosin.5. The monoamine oxidase inhibitors, clorgyline, pargyline and deprenyl had at least a ten fold lower affinity at the rabbirt cortex I2 site as compared to their known affinity at monoamine oxidase suggesting that the I2 site is not related to the active site of the enzyme, monoamine oxidase. In addition, the peripheral benzodiazepine ligands, PK-11195 or Ro 5-4864 both had very low affinities at the I2 site in rabbit cortex suggesting that the [3H]-idazoxan binding was not to the peripheral benzodiazepine binding site.

Adrenergic alpha-Antagonists↗
PubMed1990

Primary structure of rat monoamine oxidase A deduced from cDNA and its expression in rat tissues.

The cDNA for rat monoamine oxidase A (MAO-A) mRNA was isolated from a liver cDNA library in lambda gt11 as the cDNA species cross-hybridizing with rat monoamine oxidase B (MAO-B) cDNA. The primary structure of the protein, deduced from the nucleotide sequence, consisted of 526 amino acid residues and its molecular mass was calculated to be 59.6 kD. The amino acid sequence shows about 70% identity with that of rat MAO-B. Northern blot analysis showed that MAO-B mRNA was expressed in various rat tissues and the highest expression was observed in heart. The MAO-B mRNA was quite different from MAO-A mRNA in the tissue-specific expression and liver had the highest level of the mRNA.

Amino Acid Sequence↗
PubMed1983

A new type of mitochondrial monoamine oxidase distinct from type-A and type-B.

The characteristics of mitochondrial monoamine oxidase (MAO) in carp liver were studied with MAO inhibitors and substrates. This enzyme was thermolabile, but was stabilized in the presence of bovine serum albumin. With clorgyline and deprenyl, single-sigmoidal curves for inhibition of the activity towards tyramine or 5-hydroxytryptamine were obtained; the sensitivities to the two inhibitors were identical. The activity towards beta-phenylethylamine was not completely inhibited by clorgyline or deprenyl, but the remaining activity was inhibited by semicarbazide and the inhibition curves by either clorgyline or deprenyl and semicarbazide were also identical to the curves with the other two substrates. These results suggest that carp liver mitochondria contain "classical" MAO and a clorgyline- and deprenyl-resistant amine oxidase and that the classical MAO does not seem to be MAO-A or MAO-B, which are present in mitochondria of most mammalian tissues.

Animals↗
PubMed1994

Deamination of aliphatic amines by type B monoamine oxidase and semicarbazide-sensitive amine oxidase; pharmacological implications.

Straight and branched chain aliphatic monoamines, which are not normal tissue constituents, are deaminated selectively by type B monoamine oxidase (MAO-B). They exhibit a high affinity towards the active site of MAO-B and this made them very useful pharmacologically. An anticonvulsant prodrug, Milacemide [2-(N-pentyl)glycinamide] is deaminated by MAO-B and this facilitates a mechanism of delivering glycine into the CNS. We have found that 2-propyl-pentylamine (2-propyl-1-aminopentane) and N-(2-propylpentyl)glycinamide are also converted by MAO-B to valproic acid and glycine both in vitro and in vivo; these compounds, however, cause severe tremor. By attaching a propargylamine group the resultant series of aliphatic propargylamine derivatives have been shown to be very potent selective MAO-B inhibitors. They are chemically quite different from most other MAO-B inhibitors, since they do not possess any aromatic structures. The relatively short chain aliphatic propargylamines, i.e. N-2-pentyl-N-methylpropargylamine and N-2-hexyl-N-methylpropargylamine, are 4 to 5 times more potent and more selective than selegiline (1-deprenyl) with respect to the inhibition of MAO-B in brain following oral administration. Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the deamination of not only longer chain aliphatic amines but also short chain aliphatic amines including methylamine. Formaldehyde is produced from methylamine by SSAO. Increased methylamine deamination may cause cellular damage in some pathological conditions, such as uraemia and diabetes. We have observed that cultured human endothelial cells are damaged by methylamine in the presence of SSAO. Inhibition of the SSAO activity completely protects these cells from the methylamine-SSAO induced damage.

Amine Oxidase (Copper-Containing)↗
PubMed1994

Functional expression of C-terminally truncated human monoamine oxidase type A in Saccharomyces cerevisiae.

The deduced amino acid sequence of human liver monoamine oxidase type A was analyzed with secondary structure programs. These analyses and comparison to other flavoproteins identified a single potential transmembrane hydrophobic peptide at the C-terminus suggesting that this peptide is a membrane anchor and that the remainder of the protein constitutes a soluble domain. Truncation of the C-terminus by 24 amino acids which are inclusive of the putative transmembrane peptide, however, gave a protein which exhibited solubility properties substantially similar to the wild type enzyme. This result indicates that the hydrophobic behavior of monoamine oxidase type A is due to more complex features than a single transmembrane anchor. The mutant enzyme expressed in yeast appears to form a disulfide bond which reduces catalytic efficiency by up to 90%. Full activity, however, can be recovered by incubation with dithiothreitol, suggesting that in the wild type enzyme the amino acid residues deleted in the mutant protein protect two cysteine residues (those involved in the formation of the disulfide bond in the mutant) from oxidation and that the deleted residues are in close proximity to the active site. The activation experiments indicated that the deleted amino acids do not contribute any catalytic residues to the active site.

Chemical Phenomena↗
PubMed1988

The mechanism by which monoamine oxidase inhibitors give rise to a non-calcium-dependent component in the depolarization-induced release of 5-HT from rat brain synaptosomes.

1. The effects of the monoamine oxidase inhibitors pargyline and nialamide on the Ca2+-dependency of [3H]-5-hydroxytryptamine release from superfused rat brain synaptosomes has been studied in order to evaluate the discrepancies that have occasionally been observed in studying transmitter release by in vivo and in vitro techniques. 2. The application of K+ pulses of low concentration (12.5-20 mM) caused an essentially Ca2+-dependent release of [3H]-5-HT. However, at K+ concentrations above 30 mM, a small non-Ca2+-dependent component appeared. 3. At high concentrations of K+ (30-55 mM), nialamide (18 microM) or pargyline (7 microM) increased the amount of [3H]-5-HT released which could be accounted for by an increase in the non-Ca2+-dependent component of release. 4. The elevation of the non-Ca2+-dependent component of release caused by the monoamine oxidase inhibitors was totally abolished by the inhibitors of the plasma membrane 5-HT carrier, chlomipramine (500 nM), citalopram (50 nM) and fluoxetine (1 microM). 5. The results suggest that the non-Ca2+-dependent component of release seen with high depolarizing concentrations of K+, particularly in the presence of monoamine oxidase inhibitors, is caused by the efflux of [3H]-5-HT through the plasma membrane carrier which seems to be activated during depolarization. 6. The significance of these findings to the physiological in vivo situation, and to the use of in vitro preparations in the study of transmitter release is discussed.

Animals↗
PubMed2000

Monoamine oxidase in amphistomes and its role in worm motility.

The quantitative assay of mitochondrial monoamine oxidase (MAO) activity revealed a higher enzyme level in Explanatum explanatum than Gastrothylax crumenifer. The specific MAO inhibitors, chlorgyline, pargyline, deprenyl and nialamide produced different degrees of interspecific inhibition. The differential effects on enzyme activity of chlorgyline and deprenyl suggests the possible existence of polymorphic forms of the enzyme, MAO-A and MAO-B, in amphistomes. These specific inhibitors also had a differential influence on the in vitro motility of amphistomes, further indicating the involvement of different forms of MAO in the oxidative deamination of biogenic monoamines which might be partly responsible for neuromuscular coordination in amphistomes. The experimental procedures used in this study could be conveniently used for quick screening and evaluation of some of the qualitative effects of anthelmintic drugs under in vitro conditions.

Animals↗
PubMed1985

Normetanephrine and metanephrine oxidized by both types of monoamine oxidase.

Both normetanephrine and metanephrine were found to be oxidized by both types of monoamine oxidase in mouse liver mitochondria. Both Km and Vmax values of type B MAO for both substrates were higher than those of type A MAO, which caused the shift of inhibition curves with clorgyline and deprenyl according to the increase in substrate concentration.

Animals↗
PubMedDate not supplied

[The role of changes in catalytic properties of brain monoamine oxidase in the response to extreme conditions (review of the literature)].

Alterations of brain monoamine oxidase (MAO) properties related to various functional states of a body are discussed. Similar reactions of the enzyme to extremal effects of different etiology were shown as well as role of alterations in metabolic response to impairment of environment and internal medium was demonstrated. Possible mechanisms responsible for specific properties of MAO under pathological conditions are discussed.

Animals↗