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PubMed2004

Synthesis and selective inhibitory activity of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives against monoamine oxidase.

A novel series of 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives 1-12 have been synthesized and investigated for the ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The new synthesized compounds 1-12 proved to be more reversible, potent, and selective inhibitors of MAO-A than of MAO-B. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds, 6 and 11. The separated enantiomers were then submitted to in vitro biological evaluation while increasing their inhibitory activity and A selectivity. The (-)-6 enantiomer shows K(i(MAO-A)) = 2 nM and SI = 165 000, (+)-6 shows K(i(MAO-A)) = 6 nM and SI = 166 666, (-)-11 shows K(i(MAO-A)) = 4 nM and SI = 80 000, and (+)-11 shows K(i(MAO-A)) = 7 nM and SI = 38 571.

Animals↗
PubMed1985

Distinct monoamine oxidase A and B populations in primate brain.

Monoclonal antibodies specific for monoamine oxidase (MAO) A and MAO B, respectively, were used to localize these enzymes in primate brain. The reagents recognized different populations of neurons: those that recognized MAO A were located in cell groups containing catecholamines, including the substantia nigra, nucleus locus coeruleus, nucleus subcoeruleus, and the periventricular region of the hypothalamus, whereas those that recognized MAO B were observed in serotonin regions, including the nucleus raphe dorsalis and nucleus centralis superior. These data illustrate the physiological independence of MAO A and B and show that neurons may be specialized for their degradative as well as their synthetic functions.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Lack of platelet monoamine oxidase activity in Cebus monkeys (Cebus albifrons).

1. Recent evidence suggests that monoamine oxidase (MAO) plays an important role modulating the extrapyramidal syndromes produced by neuroleptic drugs in both human and nonhuman primates. 2. To evaluate the possibility of using peripheral blood platelet MAO-B levels as indices of central nervous system MAO-B effects, we measured platelet MAO-B levels in Cebus monkeys that were previously tested with neuroleptics (N = 36) or drug naive (N = 6). 3. No platelet MAO-B was consistently detectable in these blood samples. 4. Thus platelet measures of MAO-B do not reliably reflect brain MAO-B function in nonhuman primates and do not offer a useful model for studying blood-brain MAO-B relationships.

Animals↗
PubMedDate not supplied

Reversal of stress-induced deficit in aggression by monoamine oxidase inhibitors.

In the present study we investigated the effect of two monoamine oxidase (MAO) inhibitors: moclobemide (selective, reversible inhibitor of MAO-type A) or selegiline (selective irreversible inhibitor of MAO-type B) on electric footshock-induced fighting behavior in normal (unstressed) and chronically stressed (14 various stressors over 16 days) rats. In rats exposed to chronic stress the number of fighting attacks was reduced by about 75%. Prolonged (once a day, for 14 days) treatment with moclobemide (50 mg/kg/day) or selegiline (2 mg/kg/day) counteracted the deficit in aggression induced by chronic stress. The findings of the present study demonstrate that the selective MAO inhibitors, moclobemide and selegiline, protect against "behavioral depression" induced by the chronic stress similarly to other classes of antidepressant drugs.

Aggression↗
PubMedDate not supplied

[Effect of some isoquinoline alkaloids on enzymatic activity of acetylcholinesterase and monoamine oxidase].

It has been shown, that some benzo[c]-phenanthridine and diisoquinoline alkaloids isolated from Chelidonium majus L. and Macleaya (Bocconia) cordata and M. microcarpa (berberine, sanguinarine, chelidonine) and of drugs ("Ukrain" and "Sanguirythrine") inhibited the enzyme activity of acetylcholinesterase from human erythrocyte and monoamine oxidase from the rat liver. All agents under study have been shown to be reversible inhibitors of the enzymatic hydrolysis of acetylthiocholine. It has been determined that chelidonine belonged to reversible inhibitors of a competitive type, all other examined agents have been demonstrated to be inhibitors of a mixed competitive-noncompetitive type, and a greater contribution to the inhibition was made by the competitive constituent. Among all examined agents berberine, sanguinarine and "Sanguirythrine" were the strongest inhibitors of this reaction and chelidonine and "Ukrain" were much weaker. All agents under study have been shown to be irreversible inhibitors of the oxidative deamination reaction of serotonine and tyramine and not to influence the oxidative deamination reaction of benzylamine as a substrate. Among the examined agents, alkaloid sanguinarine and drug "Ukrain" are the strongest inhibitors of the reaction, alkaloids berberine, sanguinarine and "Sanguirythrine" exhibit a weaker action.

Acetylcholinesterase↗
PubMed1975

Reduction of blood platelet monoamine oxidase activity in schizophrenic patients on phenothiazines.

A newly developed assay for monoamine oxidase (MAO) activity in blood platelets (serotonin used as substrate) was applied for the measurement of the enzyme activity in 76 schizophrenic patients. No significant reduction was found in the blood platelet MAO activity in a group of 33 untreated schizophrenic patients, as compared to that in the normal controls. Male patients revealed to have lower enzyme activity than females in the schizophrenic group, as we described previously in the normal subjects. Treatment with phenothiazines caused significant reduction of blood platelet MAO activity, while platelet serotonin content and platelet count appeared to be not affected by the drug treatment. The authors suggest that blood platelet MAO activity may be related to hormonal factors but not to psychiatric diagnosis of schizophrenia or constitution liable to schizophrenic illnesses.

Adolescent↗
PubMed1996

A study of monoamine oxidase activity in fetal membranes.

OBJECTIVE: To study the role of decidual monoamine oxidase (MAO)-A and -B activities before delivery, the relationship between MAO activity in fetal membranes and catecholamine (CA) concentration in amniotic fluid (AF) was determined. METHODS: Fetal membranes and AF were obtained at the time of elective Cesarean section (CS group, n = 11) and Cesarean section due to fetal distress without labor pains (FD group, n = 5). MAO-A and -B activities were radiometrically measured using 14C-5-hydroxytriptamine for MAO-A substrate and 14C-benzylamine for MAO-B substrate. CA concentrations in AF were measured by high performance liquid chromatograph with an electro-chemical detector. RESULTS: Both MAO-A and -B activities in decidua obtained from CS were significantly lower than those obtained from FD. Both norepinephrine (NE) and epinephrine (EP) concentrations were significantly lower in the CS group than the FD group. A significant positive correlation between decidual MAO-A activity and NE concentration in AF was observed. No significant correlation was observed between MAO-B activity and the concentration of NE in AF. There was no correlation between EP concentrations and MAO activities. CONCLUSION: These results suggest that CA concentration in AF may be related to the activity of MAO in fetal membranes, determined by certain physiological processes during pregnancy. It has been suggested that metabolism of monoamines in fetal membranes also plays an important role in reducing monoamine influx into maternal myometrium from the AF.

Adult↗
PubMed1992

Effect of plasma from premenstrual syndrome and control patients on human platelet and rat brain synaptosome monoamine oxidase B activity.

The present study determined the kinetic properties of platelet monoamine oxidase (MAO) in patients with premenstrual syndrome (PMS) and control subjects during the pre- and postmenstrual intervals. In addition, we investigated the effects of plasma obtained during the pre- and postmenstrual intervals from both subject groups on MAO activity in washed human platelets and rat brain synaptosomes. The Vmax of platelet MAO in postmenstrual PMS patients was significantly less than that during the premenstrual phase. Plasma from both subject groups (10-100 microliters) inhibited platelet and synaptosomal MAO in a dose-dependent manner to approximately the same degree at each time interval. The results indicate that although human plasma contains endogenous substances which inhibit MAO activity, alterations in their concentration are probably not responsible for the previously reported transient changes in platelet MAO activity in PMS.

Animals↗
PubMed1991

Pharmacokinetics of monoamine oxidase inhibitors.

Few studies on the pharmacokinetics and plasma drug levels of monoamine oxidase (MAO) inhibitors have been performed, despite several decades of clinical use. Older MAO inhibitors such as tranylcypromine produce neuronal accumulation of neurotransmitter amines as a consequence of functionally irreversible MAO inhibition. Typically, these agents are cleared from the body rapidly, so plasma drug levels are not correlated with MAO inhibition. However, recent research has demonstrated that tranylcypromine can produce direct and reversible pharmacologic effects, as well as clinical mood effects, that appear more closely related to transient plasma tranylcypromine levels than to the degree of MAO inhibition. In addition, a new generation of reversible MAO inhibitors is now being introduced. The antidepressant actions of these latter agents will almost certainly be directly influenced by pharmacokinetic factors. This review summarizes the existing pharmacokinetic literature on tranylcypromine, phenelzine, moclobemide, and selegiline. These drugs and others like them promise to become increasingly important in modern psychopharmacologic practice.

Humans↗
PubMed1982

REM sleep suppression induced by selective monoamine oxidase inhibitors.

The effects of 4 weeks of treatment with the selective monoamine oxidase (MAO) inhibiting antidepressant clorgyline and pargyline on the sleep of affectively disordered patients were studied. Both inhibitors resulted in near total suppression of REM sleep, a decrease in total sleep time, and an increase in the percent of stage 2 sleep. Clorgyline also increased awake time and decreased total recording period and sleep latency. In general, changes were greater for clorgyline than for pargyline and were about 50% slower to return to baseline after clorgyline compared to pargyline discontinuation. The results were consistent with the hypothesis that selective inhibition of the MAO type A, as produced by clorgyline, is sufficient to induce marked sleep changes. MAO inhibitor-induced receptor changes are proposed to account for the time course of the REM suppression and the REM rebound observed upon withdrawal.

Adult↗
PubMed1981

The effect of DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) on monoamine oxidase activities in tissues of the rat.

The in vitro inhibition of monoamine oxidase (MAO) in rat liver, and of the clorgyline-resistant amine oxidase (CRAO) in rat heart and aorta, by DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) has been studied. Inhibition of each enzyme activity was independent of prolonged preincubation, was reversed by dialysis, and also Ackermann-Potter plots were consistent with reversible inhibition. Simple linear competitive inhibition of MAO-A and MAO-B was observed, with Ki values of 6 x 10(-6) and 8 x 10(-5) M, respectively. CRAO was inhibited in a mixed, non-competitive manner (Ki of 3.2 x 10(-5) and 7.8 x 10(-6) M in heart and aorta, respectively) which conformed to a kinetic model in which the binding of DSP-4 to CRAO increased the affinity of substrate binding, but prevented product formation. The possible significance of these results for the in vivo actions of the drug is discussed.

Amines↗
PubMed1992

Relationship between platelet monoamine oxidase B activity and alleles at the MAOB locus.

Genetic variations in monoamine oxidase (MAO)-B activity have been proposed to have a contributory role in several neurologic and psychiatric diseases. Variations in activity could affect rates of degradation of exogenous amines, including toxins, precursors of toxins (like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), or false transmitters, and of endogenous amines, such as neurotransmitters. In this study a highly polymorphic (GT)n repeat element was used to mark alleles at the MAOB locus. The MAOB allele status and levels of platelet MAO-B activity were determined for 41 control males. No correlation was noted between specific alleles and levels of MAO-B activity in this sample set. This suggests that the structural gene for MAOB is not usually the primary determinant of activity levels in platelets.

Adult↗
PubMed1990

Studies of the in vitro oxidation of 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol and its dehydration product 1,2,3,6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl) pyridine by human monoamine oxidases A and B.

The ability of highly purified preparations of human monoamine oxidase A and B (MAO A and B) to utilize 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol (MMPP) and its dehydration product 1,2,3,6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl) pyridine (TMMP) as substrates was investigated. The results showed that TMMP was a substrate for both forms of MAO with Km,app values of approximately 60 microM. However, MAO B had a Vmax,app for TMMP about 30-fold greater than MAO A. Additional studies revealed that MMPP was a poor substrate of only MAO B (Km,app = 9.5 mM) and that acid treatment of MMPP led to the formation of a product that could be readily oxidized by both MAO A and B. Similar acid pretreatment of TMMP yielded a product that was a much poorer substrate for MAO B than the parent compound. These results may partially explain why orally administered MMPP produces neurotoxicity in monkeys and TMMP fails to induce chemical parkinsonism.

Female↗
PubMed1993

Synthesis and characterization of 11C-labeled fluoroclorgyline: a monoamine oxidase A specific inhibitor for positron emission tomography.

A new radioligand for monoamine oxidase type A (MAO-A), [11C]fluoroclorgyline, was synthesized from its desmethyl precursor by N-methylation reaction using [11C]methyl iodide with a radiochemical yield of 75-85%. The radiochemical purity of the product was more than 99% and the specific radioactivity was 7.4-18.5 GBq/micromol. The in vivo tissue distribution studies of [11C]fluoroclorgyline in mice demonstrated its high initial uptake and prolonged retention in the brain, comparable to those of [11C]clorgyline. A selective interaction with MAO-A in the accumulation of [11C]fluorclorgyline was confirmed by a competition experiment performed with the MAO-A specific inhibitor,clorgyline, and MAO-B specific inhibitor, l-deprenyl. These very desirable characteristics of [11C]fluoroclorgyline suggested that its 18F labeled counterpart, [18F]fluoroclorgyline, would have great potential as a longer-lived alternative to 11C labeled clorgyline for in vivo studies of MAO-A in the human brain with positron emission tomography (PET).

Animals↗
PubMed1994

Effects of monoamine oxidase inhibitors and dopamine agonists on the behavior of mammal- and frog-eating snakes.

Skin mucus of the frog, Xenopus laevis, induces climbing and attenuates tongue flicking in Nerodia sipedon; these effects are induced alone and are potentiated by L-deprenyl, a monoamine oxidase type B inhibitor (MAO-Bi), but not by clorgyline, an MAO type A inhibitor (MAO-Ai). Both MAO-A and MAO-B metabolize dopamine, with MAO-B having the higher affinity; MAO-A selectively metabolizes serotonin and norepinephrine and MAO-B is selective for phenylethylamine. It was hypothesized that clorgyline and L-deprenyl would differentially modulate tongue flicking and climbing in frog-eating (Nerodia erythrogaster) and mammaphagous (Elaphe o. obsoleta) snakes, based on physiological differences between the species. L-Deprenyl caused a decrease in tongue flicking and climbing by Elaphe and an increase in climbing by Nerodia, whereas clorgyline did not alter tongue flicking, climbing, or locomotor activity in either species. To further assess the role of dopamine, hybrid black/gray rat snakes, E. o. spiloides, were administered the D1 and D2 dopamine receptor agonists SKF 77434 (SKF 38393, N-allyl) and quinpirole, respectively. SKF 77434 and quinpirole attenuated climbing, but only SKF 77434 attenuated tongue flicking in Experiment 3; neither drug affected locomotor activity. Results suggest that dopaminergic stimulation by MAO-Bi and dopamine agonists modulates tongue flicking and climbing behaviors in snakes, and that the contrasting climbing reactions induced by MAO-Bi between Elaphe and Nerodia may be linked to quantitative differences in endogenous catecholamine levels and/or to the numbers and sensitivity of receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Selective pressor enhancement by monoamine oxidase inhibitors in conscious rats.

To compare the cardiovascular effects of chronic monoamine oxidase (MAO) A and B inhibition, rats were given s.c. injections of saline clorgyline or l-deprenyl daily for 3 weeks. Indwelling vascular catheters and a Doppler flow probe were implanted chronically to allow subsequent recording of femoral pressure, heart rate and iliac blood flow before and during the treatment while the rats were awake. On days 7 and 21, average femoral pressure were significantly higher in rats treated with either saline or l-deprenyl than in those treated with clorgyline. Pressor responses elicited by injecting graded doses of phenylephrine, angiotensin or tyramine i.v. were always accompanied by bradycardia and reduced iliac flow. Magnitude of all responses was unaltered in control rats treated with the saline vehicle. In rats treated with l-deprenyl responses to tyramine were enhanced slightly, but in those treated with clorgyline enhancement was more pronounced and included not only responses to tyramine but also those to phenylephrine and angiotensin. Because clorgyline inhibits MAO A whereas l-deprenyl inhibits MAO B our findings imply that enhanced pressor responsiveness depends on inhibition of MAO A rather than MAO B.

Animals↗
PubMedDate not supplied

Inhibition of rodent brain monoamine oxidase and tyrosine hydroxylase by endogenous compounds - 1,2,3,4-tetrahydro-isoquinoline alkaloids.

Four different noncatecholic and one catecholic tetrahydroisoquinolines (TIQs), cyclic condensation derivatives of beta-phenylethylamine and dopamine with aldehydes or keto acids, were examined for the inhibition of rat and mouse brain monoamine oxidase (MAO) and rat striatum tyrosine hydroxylase (TH) activity. Simple noncatecholic TIQs were found to act as moderate (TIQ, N-methyl-TIQ, 1-methyl-TIQ) or weak (1-benzyl-TIQ), MAO B and MAO A inhibitors. 1-Methyl-TIQ inhibited more potently MAO-A than MAO-B; the similar but more modest effect was exerted by salsolinol. Only salsolinol markedly inhibited TH activity, being competitive with the enzyme biopterin cofactor. The inhibition of MAO and TH by TIQs is discussed in relation to their ability to regulate monoamine metabolism.

Alkaloids↗