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.     

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.     

Acute effects of a monoamine oxidase inhibitor, tranylcypromine, on thermoregulation in the conscious rabbit

1. The effect of a single injection of the monoamine oxidase inhibitor, tranylcypromine, administered intravenously (20 mg/kg) or into the lateral cerebral ventricle (5-10 mg), on hypothalamic and rectal temperature, has been investigated.2. Intravenous tranylcypromine causes a significant rise in body temperature, which is due, at least in part, to cutaneous vasoconstriction; this vasoconstriction is augmented by sympathectomy. It is concluded that this vasoconstrictor effect is not mediated via the central nervous system.3. Intraventricular tranylcypromine caused a transient but significant fall in core temperature. This is interpreted as being compatible with selective augmentation of hypothalamic levels of 5-hydroxytryptamine.     

REM sleep suppression induced by selective monoamine oxidase inhibitors

The effects of 4 weeks of treatment with the selective monoamine oxidase (MAO) inhibiting antidepressants 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.     

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.     

Cell death induced by MPTP, a substrate for monoamine oxidase B

MPTP is known to cause PD symptoms in primates and in rodents. In order to exert its neurotoxicity MPTP must be converted by monoamine oxidase B into MPP(+) which is the true toxic agent. MPP(+) is taken up by the dopaminergic neurons of the substantia nigra in which it induces cell death. The present work reviews and discusses papers in which specific methods were used to determine whether cell death induced by MPTP/MPP(+) should be considered as apoptosis or necrosis. These two cell death modes may be distinguished using morphological and biochemical criteria. The effect of MPTP/MPP(+) was studied in vitro and in vivo. The results show that no univocal answer is possible. The most widespread interpretation is that MPTP/MPP(+) causes apoptosis when its neurotoxic effect is only sligh and necrosis when it is stronger. Similar considerations may be made also concerning the type of cell death occurring in the dopaminergic neurons in the substantia nigra of PD patients.     

Determination of monoamine oxidase concentrations in rat liver by inhibitor binding

The concentrations of monoamine oxidase-A and -B have been determined in mitochondria, mitochondrial outer membranes and microsomes from Sprague-Dawley and Wistar rats by determining the binding of tritium-labelled pargyline. Although the amounts of each form present depended on the source and the preparation method, this was paralleled by the specific activity such that the molecular turnover number was found to remain constant. The catalytic constants, kcat/Km, which represents the apparent second-order rate constant for the combination of enzyme and substrate, were about 0.13 and 2.1 sec-1 X microM-1 for 5-hydroxytryptamine and 2-phenethylamine, respectively, regardless of the source. Estimations of the amounts of the two forms by determining the concentrations of the inhibitors clorgyline, (-)-deprenyl, J-508 or pargyline necessary to give complete inhibition were shown to give overestimates of the true values because of the non-specific binding of these inhibitors to sites other than the monoamine oxidase active site.     

Tyramine infusions and selective monoamine oxidase inhibitor treatment

The relationship between changes in IV tyramine pressor sensitivity accompanying selective monoamine oxidase (MAO) inhibitor treatment and estimates of MAO-A and MAO-B inhibition in vivo were studied. Reductions in platelet MAO activity provided an index of MAO-B inhibition, while changes in plasma 3-methoxy-4-hydroxyphenethylene glycol (MHPG) were used as an hypothesized reflection of MAO-A inhibition. Chronic treatment with the MAO-A inhibitor clorgyline and the MAO-B inhibitor pargyline showed significant inhibition of the alternate MAO enzyme as well, although this crossover effect was greater for pargyline than clorgyline. The MAO-B inhibitor deprenyl appeared to maintain the greatest degree of MAO inhibition selectivity in vivo. Tyramine pressor sensitivity changes accompanying administration of the MAO inhibitors were highly correlated with decreases in plasma MHPG (r=0.92), supporting our previous data indicating the rank order of clorgyline > pargyline > deprenyl for enhancement of tyramine pressor sensitivity and, thus, suggesting that tyramin potentiation is primarily a function of MAO-A rather than MAO-B inhibition. Changes in plasma MHPG are suggested to provide a potentially useful clinical index of in vivo MAO-A inhibition.Presently with the Biological Psychiatry Branch, NIMH     

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.     

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.