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At least 1,369 records · Page 76Linked to original sources
PubMed1996

Synthesis and selective monoamine oxidase B-inhibiting properties of 1-methyl-1,2,3,6-tetrahydropyrid-4-yl carbamate derivatives: potential prodrugs of (R)- and (S)-nordeprenyl.

The results of previous studies have established that the monoamine oxidase-catalyzed oxidation of 1-methyl-1,2,3,6-tetrahydropyridyl derivatives bearing heteroatom substituents at C-4 generates 2,3-dihydropyridinium intermediates that undergo spontaneous hydrolysis to release the C-4 substituent and form the amino enone 1-methyl-2,3-dihydro-4-pyridone. We have attempted to adapt this metabolic pathway to the preparation of amine-containing prodrugs that may target the central nervous system which is rich in monoamine oxidase A and B. In this paper we report the synthesis and the in vitro and in vivo metabolic fate of the tetrahydropyridyl carbamate derivatives which are designed to release (S)- and (R)-nordeprenyl. These carbamates are selective monoamine oxidase A substrates. An ex vivo assay has shown that the R-enantiomer is an effective and selective inhibitor of brain mitochondrial monoamine oxidase B.

Animals↗
PubMed1981

Estradiol treatment decreases type A and increases type B monoamine oxidase in specific brain stem areas and cerebellum of ovariectomized rats.

Ovariectomized rats were given either acute (50 micrograms 12 h or 24 h before sacrifice) or chronic (2 micrograms/day for one month) subcutaneous administration of 17 beta-estradiol. The activities of both type A and type B monoamine oxidase (MAO) in the cerebellum and in the areas A1, A2, and locus coeruleus of the brain stem were determined. The activity of type B MAO was increased by acute and chronic estrogen treatment in the different areas studied, whereas that of type A MAO did not change in the areas A1 and A2 and was decreased in the locus coeruleus and the cerebellum. These results indicate a discriminative action of estrogens on different forms of monoamine oxidase.

Animals↗
PubMed1997

Inhibition of brain monoamine oxidase by adducts of 1,2,3,4-tetrahydroisoquinoline with components of cigarette smoke.

A series of adducts of 1,2,3,4-tetrahydroisoquinoline (TIQ) and some components of tobacco smoke were investigated for their ability to inhibit rat brain monoamine oxidase. 1-Cyano-TIQ (1CTIQ), N-(1'-cyanoethyl)-TIQ (CETIQ), N-(1'-cyanopropyl)-TIQ (CPTIQ), and N-(1'-cyanobutyl)-TIQ (CBTIQ) were found to act as competitive inhibitors for both MAO-A and MAO-B. Ki values ranged from 16.4 to 37.6 microM. N-(Cyanomethyl)-TIQ (CMTIQ) was not found to be an inhibitor (Ki > 100 microM). These findings may help to explain the in vivo inhibitory effects of tobacco smoke on MAO activity and the suggested protective effect of tobacco smoking against Parkinson's disease. They also appear to reinforce the usefulness of reversible MAO inhibitors in smoking cessation and abstinence. However, different results must be expected between Burley and Bright tobacco.

Animals↗
PubMedDate not supplied

[Importance of the initial monoamine oxidase activity for the development of the activating or inhibiting action of indolylhydrazides].

Effects of beta-(2-methyl indolyl-3) propionic acid hydrazide and alpha-butyl-beta-(2-methyl-5-carboxy indolyl-3) propionic acid hydrazide on the activity of monoamine oxidase were studied in rat brain in vitro. The compounds activated distinctly serotonin deamination under conditions of the enzyme inhibition, caused by pretreatment with iproniazide. The activation occurred only in the samples, which were not inhibited with iproniazide. The treatment with iproniazide prevented any alterations in content of amines, caused by the compounds in the rat brain in vivo.

Animals↗
PubMed2000

Selective inhibition of monoamine oxidase B by aminoethyl substituted benzyl ethers.

Aminoethyl 3-chlorobenzyl ether was shown previously (Ding, C.Z. and Silverman, R.B. (1993). Bioorg. Med. Chem. Lett., 3, 2077-2078) to be a potent and selective time-dependent, but reversible inhibitor of monoamine oxidase B (MAO B). Based on this result, a series of novel aminoethyl substituted benzyl ethers was synthesized and the compounds were examined as potential inhibitors of both isozymic forms of MAO. Each compound in the series inhibits both MAO A and MAO B competitively, and IC50 values for each compound were determined. In general, the B isozyme is much more sensitive to these inhibitors than the A isozyme (except for the o- and p-substituted nitro analogues), in some cases by more than two orders of magnitude. The selectivity in favor of MAO B inhibition is relatively high for all of the meta-substituted analogues and quite low for all of the ortho-substituted analogues. Having the substituent at the ortho-position is most favorable for MAO A inhibition. With MAO B the meta-analogues were, in general, more potent than the corresponding ortho- and para-analogues with respect to their reversible binding constants. The meta-iodo analogue is the most potent analogue.

Animals↗
PubMed1993

Pharmacokinetics of and monoamine oxidase B inhibition by (E)-4-fluoro-beta-fluoromethylene benzene butanamine in man.

MDL 72974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine HCl salt, CAS 120635-25-8) is a new irreversible inhibitor of the B form of monoamine oxidase (MAO-B). MDL 72974A's pharmacokinetic parameters were evaluated after administration of a single oral dose and after multiple oral doses. The concentration of parent drug was determined in plasma using a solid-liquid extraction method and gas chromatographic-mass spectrometric analysis. MDL 72974A produced significant inhibition of platelet MAO-B activity at all of the doses > or = 0.5 mg (> 95% after 1 h). The pharmacokinetic parameters showed a short plasma half-life (1 h) and a high total body clearance (Cltot) both probably due to extensive and rapid metabolism as suggested by the low urinary excretion of unchanged drug (< 1% of the administered dose). After the administration of multiple doses of MDL 72974A, a decrease in Cltot and a concomitant increase in the AUC and t1/2, was observed, probably due to a change in the elimination rate of MDL 72974A. Due to the once-a-day dosing schedule and the short plasma t1/2, no drug accumulation occurred.

Allyl Compounds↗
PubMedDate not supplied

[Multiple forms of monoamine oxidase in the growing human placenta].

A ratio between two types of monoamine oxidase (MAO) was studied in the mitochondrial fraction of growing human placenta: MAO-A which is predominant in the tissue and the minor MAO-B. Activity of MAO-A with serotonin as a substrate was statistically distinctly lower (by 22%) in placenta within early periods of pregnancy as compared which the mature placenta during the delivery time. In the growing placenta activity of MAO-B with benzylamine as a substrate reached 365% of the MAO-B activity in the mature placenta. The ratio between MAO of the A and B types was altered during pregnancy as shown by inhibitory analysis, carried out using selective inhibitors of the MAO-A and -B types--Lilly 51641 substance and deprenyl as well as with semicarbazide as an inhibitor of benzylamine oxidase. At the early periods of pregnancy the rate of placental MAO-B oxidative deamination of benzylamine was distinctly higher as compared with that during the delivery act. At the same time, content of semicarbazide-sensitive benzylamine oxidase was increased during the delivery period. Possible biological significance of alterations in the amine oxidases ratio in the growing placenta is discussed considering the known property of the MAO-B inhibitor pargyline to cause abortion within early periods of pregnancy.

Amphetamine↗
PubMed1976

Platelet monoamine oxidase in schizophrenia and manic-depressive illness.

Monoamine oxidase (MAO) is an important enzyme in the catabolism of brain biogenic amines. Platelet MAO has been reported to be moderately reduced in manic-depressive patients and markedly reduced in schizophrenic patients. This enzyme's activity has been shown to be under a large degree of genetic control and has been proposed as a 'genetic marker' in schizophrenia. A transcultural replication of the finding of low platelet MAO in schizophrenia and manic-depressive illness was carried out at the Jerusalem Mental Health Centre. Manic-depressive patients were found to have higher platelet MAO activity than schizophrenic patients, as reported previously, but control individuals were as low as the schizophrenic patients. It is unlikely that platelet MAO activity is a transculturally-valid marker for schizophrenia.

Adult↗
PubMed1985

Can Patients Safely Undergo Electroconvulsive Therapy While Receiving Monoamine Oxidase Inhibitors?

A review of the experience of monoamine oxidase inhibitors (MAOI) and anesthesia finds few well-documented complications, although theoretic risks of cardiovascular reactions are discussed. Laboratory studies and actual case experiences of patients treated with electroconvulsive therapy (ECT) and MAOI suggest that the risks have been exaggerated. It is recommended that the anesthesia usually used for ECT-methohexital, succinylcholine, and optionally atropine or glycopyrrolate-may be safely given with careful blood pressure monitoring. If cardiovascular support is required, a direct-acting sympathomimetic should be administered.

Journal Article↗
PubMed2005

Synthesis of 3-benzyl-2-substituted quinoxalines as novel monoamine oxidase A inhibitors.

A new series of 3-benzyl-2-substituted quinoxalines have been synthesized by means of microwave enhancement of nucleophilic substitution reaction involving the corresponding 2-chloroquinoxaline analogs and substituted amines or hydrazine. The synthesized compounds were evaluated for their monoamine oxidase A and B inhibitory activity by determination of their IC(50). All the newly synthesized compounds showed more selective inhibitory activity toward MAO-A than MAO-B. In addition, the acute toxicity of the synthesized compounds was determined. This work may be a fruitful matrix of the synthesis of a new series of novel MAO-A inhibitors with good safety margins.

Animals↗
PubMed1986

Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase.

This is a reversed-phase liquid-chromatographic method, with electrochemical detection, for simultaneously measuring, in plasma, the concentrations of the catecholamine precursor dihydroxyphenylalanine (DOPA); the endogenous catecholamines norepinephrine, epinephrine, and dopamine; and the deaminated catecholamine metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG). We used this method to assess effects of monoamine oxidase (EC 1.4.3.4) inhibition in humans. Plasma DHPG concentrations as determined by the present method (mean 826, SEM 61 ng/L) were similar to those found by other methods. Inhibition of monoamine oxidase (by administering deprenyl or tranylcypromine) decreased plasma DHPG by greater than 65%, plasma DOPAC by greater than 50%, and plasma DOPA by about 20%, without consistently affecting norepinephrine or epinephrine. Simultaneous measurement of DOPA, catecholamines, and DHPG may be useful for examining the synthesis, release, and intraneuronal metabolism of norepinephrine. The assay method is rapid, reliable, and simple, and it provides a more comprehensive assessment of noradrenergic nervous function than does measurement only of catecholamines.

Alzheimer Disease↗
PubMed1984

Changes in rat liver and brain monoamine oxidase activity after acute treatment with some heavy metal salts.

In in vivo and in vitro experiments the effects of some heavy metal salts (Cu, Co, Cd, Pb, Ni, Zn, Hg, As, Bi and Sn) on rat liver and brain mitochondrial monoamine oxidase (MAO) activity was studied using three different substrates (tyramine, 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (2-PEA). It was established that some of the metals (Cu, Cd, Bi) inhibited MAO activity both in vivo and in vitro experiments, others like Ni, Zn, As and Sn inhibited it only in vivo while Hg exerted inhibitory action only in vitro. The in vivo experiments showed significantly higher sensitivity of brain MAO as compared with liver MAO to the inhibitory action of metals. The same higher susceptibility was shown by liver and brain MAO-A form. It was concluded that the inhibitory effects of some heavy metal salts on MAO activity were not directly connected with their action on enzyme thiol groups but more probably with changes in the enzyme membrane surroundings in the different organs.

Animals↗
PubMed1969

Cough and cold remedies: a potential danger to patients on monoamine oxidase inhibitors.

Experiments have been carried out in healthy volunteers to study the effects of phenylpropanolamine on the blood pressure and possible interactions with monamine oxidase inhibitors.In three subjects 50 mg. of phenylpropanolamine taken orally produced a modest rise of systolic pressure. Two proprietary preparations containing this dose in a slow-release form had no significant effect on the blood pressure. In all three subjects 100 mg. of phenylpropanolamine taken orally caused a more pronounced rise of systolic pressure and a rise of diastolic pressure.In contrast, 50 mg. of phenylpropanolamine orally caused a rapid and potentially dangerous rise of blood pressure in a subject taking the monamine oxidase inhibitor tranylcypromine, and a similar acute rise of blood pressure occurred in this subject when given a proprietary cough linctus containing the same dose of phenylpropanolamine. These and other results suggest that severe hypertensive episodes are more likely to occur when preparations containing phenylpropanolamine in a free form, rather than in slow-release form, are taken by patients being treated with monoamine oxidase inhibitors.The acute rise of blood pressure due to the interaction of phenylpropanolamine and monoamine oxidase inhibitors was reversed by intramuscular injection of phentolamine.

Amino Alcohols↗
PubMed1993

Intracellular distribution of monoamine oxidase A in selected regions of rat and monkey brain and spinal cord.

Monoamine oxidase A and B (MAO A and B; EC 1.4.3.4) are integral proteins of the outer mitochondrial membrane that degrade monoamines including the neurotransmitters norepinephrine, dopamine, and serotonin. In this study, monoclonal antibodies that recognize rat or monkey MAO A were used in immunocytochemical studies to visualize the subcellular localization of this enzyme within neurons in the central nervous system of these species. The regions examined included the locus coeruleus, substantia nigra, spinal cord, and pallidostriatum, which are known to contain MAO A-positive structures. Ultrastructural studies revealed that most MAO A staining was associated with the outer membrane of mitochondria, within the cell bodies, dendrites, axons and terminals. However, some immunoreactive staining for MAO A was also observed in the rough endoplasmic reticulum in the cell bodies. Staining for mitochondrial MAO A in dendrites was observed in terminal fields of the monoamine system, including the spinal cord and the pallidostriatum. The intensity of staining also increased in the subsynaptic density. MAO A was also found associated with mitochondria in ependymal cells lining the fourth ventricle adjacent to the locus coeruleus and in the endothelial cells lining the blood vessels. Localization of MAO A in noradrenergic neurons, ependymal cells, and subsynaptic regions of dendrites in monoamine terminal fields supports the concept that this neurotransmitter-degrading enzyme may play a protective role in the central nervous system.

Animals↗
PubMed1985

Deamination of aliphatic amines by monoamine oxidase A and B studied using a bioluminescence technique.

Deamination of n-octylamine and n-decylamine has been studied in various tissues using a new bioluminescence technique. Selectivity of n-octylamine and n-decylamine as substrates for monoamine oxidase (MAO) A or B has been determined using both clorgyline and (-)-deprenyl inhibition curves and kinetic parameters. Homogenates of rat brain, liver and heart containing predominantly MAO-A or -B were prepared by preincubation for 60 min with (-)-deprenyl or clorgyline (30 nM), respectively. Human placenta (MAO-A) and platelet (MAO-B) were used as reference tissues containing only one MAO form. In tissues (rat liver, brain) containing both MAO forms in equal proportion, inhibition curve studies showed a preference of both substrates for the B form of the enzyme; however, where MAO-A was the major form (rat heart, human placenta), clorgyline was the more effective inhibitor. In the beef brain cortex n-octylamine showed marked preference for MAO-B, whereas n-decylamine was selective toward-MAO-A. Kinetic studies in general supported the picture of greater selectivity of the aliphatic amine substrates for deamination by MAO-B, as reflected by lower Km values for this enzyme type. However, n-octylamine was more selective for MAO-B than n-decylamine in both kinetic and inhibition curve studies. The deamination of these aliphatic amine substrates cannot be explained only by reference to the binary classification of MAO into types A and B.

Amines↗
PubMed1991

Characterization of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) binding sites in C57BL/6 mouse brain: mutual effects of monoamine oxidase inhibitors and sigma ligands on MPTP and sigma binding sites.

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like symptoms in humans, nonhuman primates, and mice. Several studies suggest that MPTP is metabolized by monoamine oxidase (MAO) type B to yield N-methyl-4-phenyl-pyridinium (MPP+), which is responsible for the neurotoxic effects of the drug. In the present study, the pharmacological properties of [3H]MPTP binding sites in C57BL/6 mouse brain membranes were investigated, and a possible relationship to the sigma binding sites was examined. Both equilibrium binding experiments and kinetic assays indicate that [3H]MPTP labels two distinct binding sites in C57BL/6 mouse brain. The high affinity [3H]MPTP binding sites (Kd = 13 nM) are selectively blocked by the MAO type A inhibitor clorgyline, and the residual low affinity [3H]MPTP sites (Kd = 1100 nM) display the pharmacological specificity of MAO-B binding sites. In contrast, the low affinity [3H]MPTP binding sites are blocked by the selective MAO-B inhibitor (-)-deprenyl, and the drug-specificity profile of the remaining high affinity sites is consistent with the properties of MAO-A binding sites. The affinities of several MAO inhibitors tested and of MPTP for the high affinity MPTP/MAO-A binding sites correlate well (r = 0.96) with their affinities for the sigma binding sites labeled with [(+)-[3H]-3-PPP]. The sigma receptor ligand (+)-3-PPP displays moderately high affinity for the MPTP/MAO-A binding sites but negligible affinity for MPTP/MAO-B sites. Moreover, (+)-3-PPP alters the dissociation kinetics of MPTP from the high affinity MPTP/MAO-A sites. The finding that [3H]MPTP labels MAO-B sites supports the hypothesis that the drug is a substrate for these enzyme binding sites. However, the finding that the high affinity sites, labeled by [3H] MPTP, are particularly sensitive to MAO-A inhibitors, which also display high affinity for the sigma binding sites, may suggest a possible relationship between MAO-A and sigma binding sites. In turn, the kinetic experiments imply that sigma ligands [i.e., (+)-3-PPP] may allosterically modulate the binding to MAO-A binding sites.

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