Furoxanobenzofuroxan, a selective monoamine oxidase inhibitor

Furoxanobenzofuroxan (FBF) has been previously described as an inhibitor of monoamine oxidase. Inhibition was reversible, and of a mixed competitive and non-competitive type, with a molar inhibition constant of 4 × 10^?7 M. In vivo, the drug was selective in elevating the levels of indolealkylamines but not phenylethylamines. Low doses of FBF produced significant elevation of 5-hydroxytryptamine (5-HT) in the brain of the guinea-pig, but not in the heart and liver. Noradrenaline (NA) levels in these organs were not affected at the low dose. On the other hand, an equimolar dose of tranylcypromine caused elevation of NA in the heart and brain, but had no effect on 5-HT levels. FBF was shown to be a powerful blocking agent of 5-HT in the periphery, giving it a range of properties similar to those reported for the harmala alkaloids. However, no evidence was found that FBF shared the hallucinogenic properties of harmine; in fact, FBF appeared to block the central action of 5-hydroxytryptophan, a known hallucinogen. Thus, the 5-HT antagonist activity of FBF appeared to predominate over its action in elevating 5-HT levels due to inhibition of monoamine oxidase.     

Monoamine oxidase inhibitors and whole blood, platelet and plasma monoamine oxidase.

1. Whole lysed blood monoamine oxidase activity using benzylamine as substrate, represents an addition of platelet and plasma activity. 2. Enzyme activity measured in whole lysed blood in the presence of 10(-4)M pargyline gave a value equivalent to plasma monoamine oxidase, and by subtraction gives a value for platelet enzyme activity. 3. This method of measuring platelet and plasma monoamine oxidase activities from a single whole blood sample, has the advantage of not requiring physical separation of the blood fraction.     

Clinical pharmacology of moclobemide, a new reversible monoamine oxidase inhibitor

The clinical pharmacology of the new reversible monoamine oxidase (MAO) inhibitor, moclobemide, was examined in three separate studies in healthy male volunteers. In a single oral dose study, moclobemide (25-150 mg) was rapidly absorbed from the gastrointestinal tract and had a relatively short plasma half-life (mean 1.3 h after 150 mg). A decrease in the plasma concentrations of the noradrenaline metabolite 4- hydroxy-3-methoxyphenylglycol (HMPG), however, indicated a longer time to peak pharmacodynamic effect and longer duration of activity. Assay of platelet MAO activity did not reveal any evidence of irreversible inhibition of the B form of the isoenzyme. Single oral doses of moclobemide (150 and 300 mg) significantly lowered the threshold to the cardiovascular effects ('cheese reaction') of intravenous tyramine. However, after repeated administration of 100 mg three times daily for over 2 weeks, moclobemide caused significantly less potentiation than did phenelzine (15 mg three times per day) on the cardiovascular effects of oral tyramine, a clinically more relevant model. The MAO-B inhibitor, selegiline (5 mg once daily), also lowered the oral tyramine threshold significantly. Moclobemide was generally well tolerated by these healthy volunteers.     

Some effects of a monoamine oxidase inhibitor upon changes produced by centrally administered amines

In cats treated with subcutaneous or intraperitoneal injections of the monoamine oxidase inhibitor phenylisopropylhydrazine, the effects of 5-hydroxytryptamine injected into the lateral cerebral ventricle were greatly intensified and prolonged; the effects of adrenaline were potentiated to a lesser extent. Those of noradrenaline, dopamine and tryptamine were not intensified and were prolonged to only a slight degree.     

Rhesus monkey cerebrospinal fluid amine metabolite changes following treatment with the reversible monoamine oxidase type-A inhibitor cimoxatone

The effects of cimoxatone, a reversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine, and serotonin were examined in continuously collected rhesus monkey cerebrospinal fluid (CSF). Cimoxatone, 0.5–8 mg/kg given PO, produced dose-proportionate reductions of 24-h mean CSF 3-methoxy, 4-hydroxy phenylglycol (MHPG) concentrations of 21%–52%. Homovanillic acid (HVA) concentrations also decreased 27%–55%, while CSF 5-hydroxyindoleacetic acid (5-HIAA) decreases were somewhat smaller (7%–32% from baseline). All three metabolite concentrations reached a nadir approximately 6–10 h after drug administration, and required over 40 h to gradually return towards baseline following drug discontinuation. HVA concentration reductions in particular persisted during the entire 24-h period following treatment and were the slowest to return to baseline values. CSF concentrations of cimoxatone and its MAO-inhibiting O-demethyl metabolite showed a parallel time course peaking 6–10 h after treatment and persisting for up to 24 h in the case of cimoxatone and over 48 h for its metabolite. Single simultaneous time point determinations revealed 10-to 20-fold lower concentrations of cimoxatone and its metabolite in CSF compared to plasma 2 h after treatment. MAO-B activity in platelet-rich plasma was not inhibited by 8 mg/kg cimoxatone, indicating that this drug maintains MAO-A selectivity in vivo. As cimoxatone's preferential effects on catecholamine metabolites were similar to those previously observed with the irreversible MAO-A inhibiting antidepressant, clorgyline, our results are consistent with limited clinical trials data suggesting that cimoxatone may also prove to be an effective antidepressant.     

Substrate specificity and inhibitor sensitivity of monoamine oxidase in rat kidney mitochondria.

The deamination of the substrates 5-hydroxytryptamine (5-HT), tyramine, dopamine, β-phenylethylamine and benzylamine by rat kidney mitochondrial monoamine oxidase (MAO) was studied, and kinetic constants are reported for each substrate. By the use of the selective MAO inhibitors, clorgyline and deprenyl, 5-HT and benzylamine were found to be substrates for types A and B MAO, respectively, in this tissue, whereas the other substrates were metabolized by both forms of MAO. No evidence for any significant metabolism of 5-HT or benzylamine by other amine oxidases was obtained. However, some conditions under which the carbonyl reagents semicarbazide, isoniazid and aminoguanidine may interfere with assays for MAO, without actually affecting enzyme activity directly, are described. Preincubation of kidney mitochondria with histamine resulted in a time- and oxygen-dependent irreversible inhibition of both type A and type B MAO activity; the exact nature of the inhibitory agent and its mode of action remain to be determined.     

Studies of monoamine oxidase and semicarbazide-sensitive amine oxidase. I. Inhibition by a selective monoamine oxidase-B inhibitor, MD 780236

In vitro studies of the effect of MD 780236, a selective monoamine oxidase (MAO)-B inhibitor, on a semicarbazide-sensitive amine oxidase (SSAO) in rat testis and lung showed that this compound dose-dependently inhibited SSAO activity. The extents of inhibition of MAO-A, -B and SSAO in these two rat tissues by this compound after 30 min of preincubation were found to be MAO-B greater than MAO-A greater than SSAO. This selectivity was also evident in preparations without preincubation. Degree of inhibition of SSAO was not significantly influenced by pretreatment with either 10(-3) M clorgyline, I-deprenyl or 10(-4) M SKF 525A. Inhibition of SSAO was not enhanced by varying the time of preincubation of the enzyme and the compound, indicating direct action on and reversible inhibition of SSAO. The inhibition of SSAO by MD 780236 was non-competitive with or without preincubation, with a K1 value of 110 muM. Although MD 780236 is a selective and "suicide substrate" inhibitor of MAO-B, these present results indicate that this compound may also inhibit SSAO activity, but by a mechanism different from that for MAO-B. These findings confirm an earlier hypothesis that compounds that inhibit both MAO and SSAO have totally different modes of action on these two different amine oxidases.     

Interactions between sympathomimetic amines and a new monoamine oxidase inhibitor

A relatively safe method is described for the screening of new monoamine oxidase inhibitors with respect to their potentiation of dietary and sympathomimetic amines. Studies of such a compound, Clorgyline, and its interactions with oral tyramine and phenylephrine given by mouth to three doctor-volunteers are described. Marked potentiation of the bradycardia-inducing properties of the amines was found.     

The effects of chronic treatment with amitriptyline and MDL 72394 on the control of 5-HT release in vivo

The purpose of the experiments reported were to determine whether chronic treatment with either a monoamine oxidase (MAO) inhibitor or an uptake inhibitor would increase extracellular levels of 5-HT in vivo and whether such treatment resulted in a down-regulation of the 5-HT1B-mediated decrease in extracellular levels of 5-HT. Rats were given either saline, (E)-beta-fluoromethyline-m-tyrosine (MDL 72394 0.25 mg/kg p.o.) or amitriptyline (10 mg/kg p.o.) once a day for 21 days. Twenty-four hr after the final injection, dialysis loops were implanted into the frontal cortices of these rats and basal extracellular levels of 5-HT were measured. The effect of the 5-HT1 receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole succinate (RU 24969 10 mg/kg i.p.) on the extracellular level of 5-HT was then studied. Basal levels of 5-HT in saline-treated rats was found to be 27.9 +/- 3.9 fmol/20 microliters perfusate. Chronic treatment with amitriptyline had no effect on extracellular levels of 5-HT but chronic treatment with MDL 72394 significantly increased extracellular levels of 5-HT. Chronic treatment with either MDL 72394 or amitriptyline had no significant effect on the ability of RU 24969 to reduce extracellular levels of 5-HT. These results suggest that 5-HT1B receptors are not down-regulated in response to chronically raised extracellular levels of 5-HT.     

Pharmacodynamics of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. The inhibition of monoamine oxidase B (MAO-B) by lazabemide was measured in platelets collected from 35 young (19-36 years) and 40 older (60-78 years) healthy volunteers after single (100-300 mg) and multiple (100-350 mg twice daily) oral doses respectively. 2. The relationship of the effect with plasma concentrations of the MAO-B inhibitor was defined by a sigmoid Imax-model using either a parametric or semi-parametric method for predicting plasma drug concentrations. Population parameter estimates were obtained by the expectation maximization method and a standard two-stage method. 3. At the lowest dose platelet MAO-B activity was almost completely inhibited for around 20 h. No time delay between plasma drug concentration and resulting inhibition of platelet MAO-B occurred. Low concentrations of the inhibitor produced 50% of maximum inhibition (IC50, estimates for population mean +/- s.d.: 0.48 +/- 0.89 microgram l-1 for young and 1.5 +/- 2.3 micrograms l-1 for elderly subjects). The maximum extent of enzyme inhibition attributable to lazabemide (Imax) was 94 +/- 5.1% and 96 +/- 4.5% in the young and older populations. There was no correlation between age and either Imax or IC50. 4. Model parameters describing the interaction of lazabemide with the enzyme did not change over the treatment period of 7 days.     

Isolation and characterization of a monoamine oxidase inhibitor from tobacco leaves

Recent positron emission tomography imaging studies have demonstrated a significant decrease in both monoamine oxidase A and B (MAO-A and MAO-B) activities in the brains of smokers. Normal levels of activity are observed in former smokers, suggesting the presence of one or more compounds in tobacco smoke that may inhibit these enzymes. In this paper, we report the results of efforts to identify compounds present in flue-cured tobacco leaves that inhibit MAO. The isolation procedure was guided by estimating the inhibitory properties of tobacco leaf extracts on the liver mitochondrial MAO-B-catalyzed oxidation of 1-methyl-4-(1-methylpyrrol-2-yl)-1,2,3, 6-tetrahydropyridine to the corresponding dihydropyridinium metabolite. Fractionation of extracts from flue-cured tobacco leaves led to the isolation of a competitive inhibitor of human MAO-A (K(i) = 3 microM) and MAO-B (K(i) = 6 microM), the structure of which could be assigned by classical spectroscopic analysis and confirmed by synthesis. This information may help to provide insights into some aspects of the pharmacology and toxicology of tobacco products.     

Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase

Methylene blue (MB) has been shown to act at multiple cellular and molecular targets and as a result possesses diverse medical applications. Among these is a high potency reversible inhibition of monoamine oxidase A (MAO-A) that may, at least in part, underlie its adverse effects but also its psycho- and neuromodulatory actions. MB is metabolized to yield N-demethylated products of which azure B, the monodemethyl species, is the major metabolite. Similar to MB, azure B also displays a variety of biological activities and may therefore contribute to the pharmacological profile of MB. Based on these observations, the present study examines the interactions of azure B with recombinant human MAO-A and -B. The results show that azure B is a potent MAO-A inhibitor (IC₅₀ = 11 nM), approximately 6-fold more potent than is MB (IC₅₀ = 70 nM) under identical conditions. Measurements of the time-dependency of inhibition suggest that the interaction of azure B with MAO-A is reversible. Azure B also reversibly inhibits the MAO-B isozyme with an IC₅₀ value of 968 nM. These results suggest that azure B may be a hitherto under recognized contributor to the pharmacology and toxicology of MB by blocking central and peripheral MAO-A activity and as such needs to be considered during its use in humans and animals.