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PubMed1981

Increased platelet monoamine oxidase activity in affective disorders.

Platelet monoamine oxidase activity was determined in 52 unipolar depressive patients, 26 patients with bipolar affective disorder and 48 controls using phenylethylamine as substrate. Unipolar depressive patients of either sex and bipolar depressive women showed significantly higher platelet MAO activity than controls. Women had higher activity than men. Neither age nor serum lithium level correlated with enzyme activity and there was no significant change in activity after the institution of lithium treatment.

Adult↗

PubMed2004

Monoamine oxidase inhibitors from Gentiana lutea.

Three monoamine oxidase (MAO) inhibitors were isolated from Gentiana lutea. Their structures were elucidated to be 3-3''linked-(2'-hydroxy-4-O-isoprenylchalcone)-(2'''-hydroxy-4''-O-isoprenyldihydrochalcone) (1), 2-methoxy-3-(1,1'-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one and 5-hydroxyflavanone. These compounds, and the hydrolysis product of 1, displayed competitive inhibitory properties against MAO-B which was more effective than MAO-A.

Animals↗

PubMed2002

Monoamine oxidase: radiotracer development and human studies.

Monoamine oxidase (MAO) is an integral protein of outer mitochondrial membranes and occurs in neuronal and nonneuronal cells in the brain and in peripheral organs. It oxidizes amines from both endogenous and exogenous sources, thereby influencing the concentration of neurotransmitter amines as well as many xenobiotics. It occurs in two subtypes, MAO A and MAO B, which are different gene products and have different substrate and inhibitor specificities. Both MAO A and B can be imaged and quantified in the living human brain using positron emission tomography (PET) and radiotracers labeled with carbon-11. PET studies have been carried out to measure the effects of age, MAO inhibitor drugs, tobacco smoke exposure, and other factors on MAO activity in the human brain.

Aging↗

PubMed1984

Studies of selective and reversible monoamine oxidase inhibitors.

Several selective and reversible monoamine oxidase inhibitors (MAOIs) have recently become available. Preliminary studies suggest that these compounds have antidepressant effects and may offer significant safety and side effect advantages over classical MAOIs. Pilot studies with 1-deprenyl, a selective MAO-B inhibitor, indicate that it may be most effective for patients with nonendogenous depression and for those (endogenous or nonendogenous) who present with certain reverse vegetative signs. The drug appears ineffective in depressed patients with associated panic attacks and phobic symptoms. An alternative approach in the development of safer, effective MAOIs is the use of rapidly reversible MAO-A inhibitors, such as moclobemide, that carry less risk of a hypertensive reaction and yet appear to be effective antidepressants. As selective MAO-A and MAO-B inhibition may be effective in different depressive subtypes and may have different side effects, these drugs are valuable pharmacologic probes for studying the biochemical bases of depressive disorders.

Animals↗

PubMed1987

The current status of monoamine oxidase and its inhibitors.

The enzyme monoamine oxidase (MAO) plays an important role in the inactivation of both dietary amines and also of neurotransmitter amines. A study of the properties of irreversible inhibitors of this enzyme suggests that the enzyme exists in two broad types--MAO-A and MAO-B. Although irreversible inhibitors of MAO were once widely used as antidepressant agents, they fell from favour because of adverse reactions after the ingestion of amine-containing foodstuffs ("the cheese reaction"). However, these inhibitors (phenelzine and tranylcypromine) are probably best for the treatment of atypical depression providing the patient is aware of dietary reactions. A new series of reversible, MAO-A selective inhibitors are being developed which do not exhibit serious dietary interactions. These reversible inhibitors show promise as rapidly acting antidepressant agents. An atypical irreversible MAO-B selective inhibitor, selegiline (deprenyl) does not exhibit an adverse reaction on the ingestion of amine-containing foods. This drug has been used as an adjuvant in the treatment of Parkinson's disease since it allows the dose of L-dopa to be reduced by approximately 25%. More important, selegiline may slow the degeneration of dopaminergic neurons that is characteristic of Parkinson's disease.

Allylamine↗

PubMed2005

Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis.

Monoamine oxidases A and B (MAO A and B) catalyze the degradation of neurotransmitters and represent drug targets for the treatment of neurodegenerative disorders. Rasagiline is an irreversible, MAO B-selective inhibitor that has been approved as a novel anti-Parkinson's drug. In this study, we investigate the inhibition of recombinant human MAO A and MAO B by several rasagiline analogues. Different substituents added onto the rasagiline scaffold alter the binding affinity depending on the position on the aminoindan ring and on the size of the substituent. Compounds with a hydroxyl group on either the C4 or the C6 atom inhibit both isozymes, whereas a bulkier substituent such as a carbamate is tolerated only at the C4 position. The 1.7 A crystal structure of MAO B in complex with 4-(N-methyl-N-ethyl-carbamoyloxy)-N-methyl-N-propargyl-1(R)-aminoindan shows that the binding mode is similar to that of rasagiline with the carbamate moiety occupying the entrance cavity space. 1(R)-Aminoindan, the major metabolic product of rasagiline, and its analogues reversibly inhibit both MAO A and MAO B. The crystal structure of N-methyl-1(R)-aminoindan bound to MAO B shows that its aminoindan ring adopts a different orientation compared to that of rasagiline.

Crystallography, X-Ray↗

PubMed1975

Modification of rat uterine monoamine oxidase activity by steroid hormones.

The monoamine oxidase (MAO) activity in the ovariectomized rat uterus was significantly increased above control levels in animals given testosterone: 33% (P smaller than 0.01) with tryptamine or 34% (P smaller than 0.05) with tyramine as substrate. Activity was also higher in hydrocortisone-treated animals: 30% (P smaller than 0.05) with tyramine or 25% (P smaller than 0.05) with tryptamine as substrate. Progesterone injection increased MAO activity toward tyramine by 20% but towards tryptamine by only 8%. The differences are not statistically significant but are believed to be real since they were reproducible. MAO activity in oestradiol-treated animals was 11% less than in the controls for both substrates. Although they are not significant differences, they were reproducible. No change in MAO activity was observed in the cerebellum, hypothalamus or anterior pituitary of ovariectomized rats after steroid treatment. At oestrus the enzyme activity in the uterus was lower than at dioestrus or prooestrus when beta-phenylethylamine was the substrate. When 5-hydroxytryptamine was used to measure enzyme activity, the same values were found at oestrus, dioestrus and prooestrus. Ovariectomy did not cause any changes in MAO activity in any of the tissues. Effects of the steroids in vivo were probably not due to a direct action on the enzyme since only at high concentration did they have any effect on the mitochondrial enzyme activity of the uterus in vivo.

5-Hydroxytryptophan↗

PubMed1996

Identification of a region important for human monoamine oxidase B substrate and inhibitor selectivity.

Monoamine oxidase (MAO) A and B are flavoenzymes that catalyze the oxidative deamination of biogenic and xenobiotic amines. To search for domains that confer substrate and inhibitor selectivities, two chimeric proteins were constructed and expressed in yeast. The kinetic constants and IC50 values were determined for these chimeric enzymes using MAO-A/B selective substrates and inhibitors. Replacement of MAO-A amino acids 161-375 with the corresponding region of MAO-B, termed AB(161-375)A, converted MAO-A catalytic properties to MAO-B like ones. The specificity constants (k(cat)/K(m))for the oxidation of beta-phenylethylamine (PEA) (1.6 x 10(5) s-1 M-1) and benzylamine (2.4 x 10(4) s-1 M-1) by AB (161-375)A were similar to wild-type MAO-B (PEA, 8 x 10(5)s(-1) M(-1); benzylamine, 4.9 x 10(4) s(-1) M(-1). Serotonin (5-HT), a preferred substrate for MAO-A, was not oxidized by AB(161-375)A or wild-type MAO-B. Furthermore, (AB161-375)A was more sensitive to the MAO-B specific inhibitor deprenyl (IC50 2.7 +/- 0.4 x 10(-8) M) than to the MAO-A specific inhibitor clorgyline (IC50 5.4 +/- 0.8 x 10(-7) M). However, the reciprocal chimera in which a MAO-B segment was replaced with the corresponding region of MAO-A, termed ++(+BA152-366B), lacked catalytic activity. The lack of catalytic activity was not due to aberrant expression but rather an inactive protein as demonstrated by Western blot analysis. These results demonstrate that MAO-B amino acids 152-366 contain a domain(s) that confers substrate and inhibitor selectivity.

Base Sequence↗

PubMed1995

Structure/function relationships of mitochondrial monoamine oxidase A and B chimeric forms.

Monoamine oxidases (MAO) A and B show a high degree of amino acid similarity. Apart from the NH2-terminus, which contains an ADP-binding consensus sequence, little is known about their structural features or the sequences involved in the binding of substrates. In the present paper, we have studied the structure/function relationships of MAOs by constructing 18 different chimeric forms of MAO, engineered by moving progressively the junction between the NH2-terminus of one MAO form with the COOH-terminus of its isoenzyme. After transient expression in HEK-293 cells, the properties of these chimeric enzymes were investigated using both selective and nonselective substrates and inhibitors. Whereas exchange of the ADP-binding sequence did not modify the catalytic properties of either MAO isoforms, chimeras with increasing length of the NH2-terminus of MAO-A (up to residue 256) showed a marked decrease in affinity towards the MAO-B substrate phenylethylamine and the inhibitor N-(2-aminoethyl)-5-chloro-2-pyridine carboxamide . HCl (lazabemide) when compared to wild-type MAO-B. No major changes were observed in the kcat values of these chimeras. From the data obtained, two sequences, i.e. 62-103 and 146-220, appeared of particular importance in constituting the binding site of MAO-B. On the other hand, the catalytic properties and specificity of MAO-A appeared to be relatively insensitive to substitution of both the NH2- (up to position 112) and COOH-termini (from residue 395) of MAO-A with the corresponding MAO-B sequences. However, further modification of the central 283-residue sequence of MAO-A did not appear compatible with enzymic activity. None of the engineered chimeras showed a shift in specificity from one isoform to the other.

Base Sequence↗

PubMed1988

Design and early clinical evaluation of selective inhibitors of monoamine oxidase.

1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC = C(R)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors of MAO type B which in vivo show high inhibitory potency against the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and monkeys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R = 3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, substantially decreased urinary MHPG and plasma DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1978

Platelet monoamine oxidase activity in Huntington's chorea.

The possibility that genetically determined abnormalities in the monoamine oxidase of certain central nervous system aminergic neurones may play a part in the pathology of Huntington's chorea was investigated using human platelet monoamine oxidase. Significantly elevated monoamine oxidase activity was found in male patients compared to control subjects suggesting this may be a screening test for this disorder. Low monoamine oxidase activity was associated with a better clinical response to drugs.

Adult↗

PubMed2005

Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo.

Recent clinical evidence indicates that the broad spectrum anticonvulsant drug lamotrigine is effective against the depressive phase of bipolar illness and the difficult to treat rapid cycling form of the disorder. However, the molecular mechanism underlying this therapeutic action remains uncertain. Given that inhibition of the A-type of monoamine oxidase (MAO) is a proven antidepressant mechanism, we investigated the effects of lamotrigine on MAO activities in vitro and on monoamine disposition in vivo. In vitro, lamotrigine inhibited rat brain MAO activities with Ki values (MAO-A, 15 microM; MAO-B, 18 microM) potentially within the therapeutic range for this drug. The effects of lamotrigine on the MAO-A activities of rat brain and human liver preparations were almost identical suggesting minimal species or tissue variation. In contrast, there was no (MAO-A) or minimal (MAO-B) reduction in brain MAO activities when assayed ex vivo following the administration of lamotrigine to rats. In vivo brain microdialysis failed to detect meaningful alterations in extracellular hippocampal or frontal cortex monoamine concentrations. Furthermore, lamotrigine did not modulate oral tyramine-induced hypertension in rats or 5-hydroxytryptophan-induced head shaking in mice, providing strong evidence that the drug does not perturb monoamine metabolism in vivo. The absence of observable effects of lamotrigine on monoamine disposition in vivo may be explained by the competitive and highly reversible nature of the interaction of lamotrigine with MAO isoforms. Thus, altered monoamine metabolism in vivo is unlikely to account for the antidepressant action of the drug in bipolar depression.

5-Hydroxytryptophan↗

PubMed1991

Gene cloning of the maoA gene and overproduction of a soluble monoamine oxidase from Klebsiella aerogenes.

We cloned the structural gene for monoamine oxidase (maoA) from Klebsiella aerogenes into a pKI212 vector in an maoA mutant strain of K. aerogenes. Deletion analysis and complementation tests of the recombinant plasmid showed that the maoA gene was located entirely within a 4.1-kb segment. In an maoA mutant strain harbouring the cloned maoA gene, synthesis of monoamine oxidase was induced by addition of tyramine and related compounds. Transfer of a plasmid containing the maoA gene into a monoamine oxidase-producing strain of K. aerogenes W70 resulted in about a 30- to 40-fold increase in total production of the enzyme. When cells of K. aerogenes carrying the plasmid containing the maoA gene were grown with tyramine, more than 85% of the monoamine oxidase was produced in soluble form, whereas the parent strain W70 produced most monoamine oxidase as the membrane-bound form.

Chromosome Deletion↗

PubMed1989

Deuterium isotope effect measurements on the interactions of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with monoamine oxidase B.

Kinetic deuterium isotope effects for the noncompetitive, intermolecular monoamine oxidase B-catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the corresponding 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+ were found to be 3.55 on Vmax and 8.01 on Vmax/Km with MPTP-6,6-d2 as the deuterated substrate. Similar values were obtained with MPTP-2,2,6-d4 and MPTP-CD3-2,2,6,6-d4. The deuterium isotope effect for the electrochemical oxidation of 1 mM MPTP-2,2,6,6-d4 was only 1.35. These results indicate that the monoamine oxidase B-catalyzed oxidation of this substrate may not proceed via a reaction pathway involving alpha-carbon deprotonation of an aminium radical intermediate. Isotope effect measurements also established that the rate of inactivation of monoamine oxidase B by MPTP is unaffected by replacement of the C-6 methylene protons with deuterons, but is retarded by replacement of the C-2 methylene protons (DKi = 1.9). The mechanism-based inactivation of monoamine oxidase B by MPTP, therefore, is likely to mediated by a species derived from the enzyme-generated 2,3-dihydropyridinium oxidation product.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1997

Evaluation of monoamine oxidase B inhibition by fluoxetine (Prozac): an in vitro and in vivo study.

Inhibition of monoamine oxidase B was investigated both in vitro and in vivo in rats by using the radioligand, N-(6-[18F]fluorohexyl)-N-methylpropargylamine ([18F]FHMP). Binding affinities of five compounds, deprenyl, clorgyline, fluoxetine, norfluoxetine and citalopram were studied. Fluoxetine and norfluoxetine showed affinities of 17 and 13 microM for monoamine oxidase B, respectively. Acute doses of fluoxetine and norfluoxetine (20 mg/kg) also significantly inhibited (10 to 15%) the binding of the radioligand in vivo while citalopram showed lower affinity (140 microM) for monoamine oxidase B and little effect in vivo. The in vivo effects of the various drugs were directly comparable to their in vitro affinities for binding to monoamine oxidase B in the correlation plot of percent control in vivo binding of [18F]FHMP and binding affinity, -logIC50 (R2 = 0.989). These results provide evidence for a potential role of monoamine oxidase B inhibition in the therapeutic effects of Prozac.

Animals↗

PubMed1980

Properties of monoamine oxidase in control and Lesch-Nyhan fibroblasts.

Monoamine oxidase activity of the A type was measured in homogenates of cultured human skin fibroblasts. Twenty-four control lines had activities ranging over fifty-fold with an apparent bimodal distribution. Activity in fibroblasts from 20 patients with the Lesch-Nyhan syndrome fell in the low portion of the normal distribution with a mean activity about 50% that of the control mean (p < 0.05). In a subgroup of control and Lesch-Nyhan lines with levels of enzyme activity from 0.9 to 179 pmol/min/mg protein, monoamine oxidase was similar with respect to apparent Km for tryptamine, thermal stability at 56 C, and sensitivity to clorgyline. Thus the lower mean levels of activity observed in the Lesch-Nyhan as compared to control fibroblasts were not associated with other altered properties of the enzyme. The bimodal distribution of enzyme activity suggests that a genetic polymorphism for monoamine oxidase may control levels of activity expressed in fibroblasts.

Adolescent↗

PubMed1983

Endogenous inhibitors of monoamine oxidase present in human cerebrospinal fluid.

Inhibitory activity against the enzyme monoamine oxidase is present in low molecular weight fractions (less than 100,000) of human cerebrospinal fluid. These endogenous substances of different molecular weights (3000 to more than 35,000) act like monoamine oxidase inhibitor drugs to inhibit both type A and type B monoamine oxidase.

Animals↗

PubMed1989

Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A.

Moclobemide belongs to a new generation of short-acting, reversible, monoamine oxidase (MAO) inhibitors. In vitro (rat brain homogenates) moclobemide inhibits MAO-A selectively with lower potency than many of the reference MAO inhibitors. However, when measured ex vivo in the rat, the potency of moclobemide is similar to that of reference compounds. In vivo the drug induces a dose-dependent, short-lasting (8-16 hr) and preferential inhibition of MAO-A in the brain and both MAO-A and MAO-B inhibition in extracerebral organs (liver, small intestine and kidney). In the extracerebral tissues of the rat moclobemide induces marked peripheral MAO-B inhibition due to rapid and extensive biotransformation of its morpholine ring. The active molecular species is probably the metabolite Ro 16-6491. The moderate MAO-B inhibition measured after moclobemide intake in human platelets indicates that only minor amounts of Ro 16-6491 are formed in humans. Virtually all metabolites of moclobemide so far identified have been tested in vitro and ex vivo in the rat and proved to be either equipotent or, mostly, less effective than moclobemide as MAO-A inhibitors. In liver homogenates of moclobemide-treated rats MAO-A activity recovers during dialysis or simple incubation at 37 degrees C, suggesting a biodegradation of moclobemide and/or the moclobemide-derived active metabolite(s) by MAO itself or a slow dissociation of the active inhibitory species from the enzyme. Similar to other MAO-A inhibitors, moclobemide induces an increase in the rat brain levels of 5-hydroxytryptamine, norepinephrine and dopamine and a concomitant decrease of their deaminated metabolites. These effects are of short duration (8-16 hr) and parallel the time course of MAO-A inhibition. Moclobemide administered subchronically down-regulates beta adrenoceptors as shown by binding experiments with brain cortical membranes using dihydroalprenolol as ligand. In vitro MAO inhibition by moclobemide is specific in that the compound does not affect other amine oxidases or monoamine uptake mechanisms; furthermore, it does not interact with various neurotransmitter or drug receptor sites. In conclusion, a large body of preclinical evidence characterizes moclobemide as a short-acting and reversible MAO-inhibitor. The neurochemical profile of moclobemide indicates clearly that this nonhydrazine nonhepatotoxic MAO-A inhibitor represents a novel and safe drug for treatment of affective disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗