Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor

STUDY OBJECTIVE: To investigate the tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline after once-daily oral administration of single or repeated doses. DESIGN: A randomized, double-blind, placebo-controlled, three-way, single-dose study and a randomized, double-blind, placebo-controlled, repeated-dose study. SETTING: Clinical research center in France. SUBJECTS: Healthy male volunteers aged 18-40 years (12 in the single-dose study, 24 in the repeated-dose study). INTERVENTION: In the single-dose study, subjects received, in a randomized sequence, single doses of placebo, rasagiline 1 mg, and rasagiline 5 mg; or placebo, rasagiline 2 mg, and rasagiline 10 mg. Six subjects received an additional single dose of rasagiline 20 mg. There was a 2-week washout period between each dose. In the repeated-dose study, subjects were randomized to receive rasagiline 2 mg, 5 mg, or 10 mg, or placebo once/day for 10 days. MEASUREMENTS AND MAIN RESULTS: To assess tolerability and safety, patients underwent physical examinations, vital sign measurements, 12-lead electrocardiograms, clinical laboratory testing, and bleeding time studies. To determine platelet monoamine oxidase type B (MAO-B) activity and rasagiline pharmacokinetics, blood and urine samples were taken. In the single-dose study, rasagiline 1-20 mg was well tolerated. Each dose significantly inhibited platelet MAO-B activity. In the repeated-dose study, all doses of rasagiline were well tolerated; almost full inhibition of platelet MAO-B activity was achieved with each rasagiline dose. CONCLUSION: Rasagiline is well tolerated at doses up to 20 mg once/day and is a potent inhibitor of platelet MAO-B in humans.     

Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B

1. Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(-) enantiomer is relatively inactive in the tissues examined. 3. The in vitro IC(50) values for inhibition of rat brain MAO activity by rasagiline are 4.43+/-0.92 nM (type B), and 412+/-123 nM (type A). The ED(50) values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1+/-0.01, 0.042+/-0.0045 mg kg(-1) respectively for MAO-B, and 6.48+/-0.81, 2.38+/-0.35 mg kg(-1) respectively for MAO-A. 4. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED(50) values of 0.014+/-0.002 and 0.013+/-0.001 mg kg(-1) respectively. 5. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.     

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.     

Cardiovascular baroreceptor activity and selective inhibition of monoamine oxidase

Cardiovascular baroreceptor responsiveness of conscious rats treated with selective inhibitors of monoamine oxidase (MAO) types A and B was determined by measurement of blood pressure (BP) and heart rate (HR) responses to intravenous injection of phenylephrine and sodium nitroprusside. Treatment with selegiline (1 or 5 mg/kg p.o. daily for 7 days) did not significantly modify resting levels of BP and HR, lower or upper HR plateau levels, or HR/BP gain. Treatment with clorgyline (2 mg/kg p.o. daily for 7 days) increased HR/BP gain but also did not modify resting BP or HR, or lower and upper plateau levels of HR. The results are compatible with an effect of MAO-A inhibition to modify monoamine levels in medullary areas participating in CNS control of blood pressure.     

Aliphatic propargylamines: potent, selective, irreversible monoamine oxidase B inhibitors.

A series of aliphatic propargylamine derivatives has been synthesized. Some of them possess highly potent, irreversible, selective, inhibitory activity toward monoamine oxidase B (MAO-B). The potency of the inhibitors is related to chain length and substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO inhibitory activity as assessed in vitro increased as the aliphatic carbon chain length increased. Substitution of a hydrogen by hydroxyl, carboxyl, or carbethoxyl groups at the aliphatic chain terminal or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced the inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent than those with longer chains in inhibiting brain MAO-B activity in vivo especially after oral administration. Chronic administration of low doses of the aliphatic propargylamines caused a slight cumulative inhibition of MAO-A activity in the mouse brain. These MAO-B inhibitors appear to be nontoxic, and they do not possess an amphetamine-like moiety in their structure as is the case for deprenyl. We expect that these aliphatic propargylamines may be useful in the treatment in certain neuropsychiatric disorders.     

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.     

Simple,potent, and selective pyrrole inhibitors of monoamine oxidase types A and B

N-Benzyl- and N-propargyl-1H-pyrrole-2-carboxyamides and some related methylenamines were synthesized and tested for their monoamine oxidase types A and B inhibitory activity. 2-(N-Methyl-N-propargylaminomethyl)-1H-pyrrole (24) was the most potent MAO-A inhibitor of the series [K(i)(MAO-A) = 0.0054 microM], but it was not selective. Inhibitors N-4-fluorobenzyl-1H-pyrrole-2-carboxamide (12) and N-cyclohexylmethyl-1H-pyrrole-2-carboxamide (25) showed the highest MAO-A selectivity indexes (SI) corresponding to 2025 and >2500, respectively, while 2-(N-methyl-N-benzylaminomethyl)-1H-pyrrole (21) was the most selective MAO-B inhibitor, having an SI of 0.0057.     

Antioxidant activity of the monoamine oxidase B inhibitor lazabemide

Free radical-induced damage to lipid and protein constituents of neuronal membranes contributes to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). The development of an effective inhibitor of oxidative stress represents an important goal for the treatment of AD. In this study, the intrinsic antioxidant activity of lazabemide, a potent and reversible inhibitor of monoamine oxidase B (MAO-B), was tested in a membrane-based model of oxidative stress. Under physiologic-like conditions, lazabemide inhibited lipid peroxidation in a highly concentration-dependent manner. At low, pharmacologic levels of lazabemide (100.0 nM), there was a significant (P < 0.001) and catalytic reduction in lipid peroxide formation, as compared with control samples. The antioxidant activity of lazabemide was significantly more effective than that of either vitamin E or the MAO-B inhibitor, selegiline. The ability of lazabemide to inhibit oxidative damage is attributed to physico-chemical interactions with the membrane lipid bilayer, as determined by small angle x-ray diffraction methods. By partitioning into the membrane hydrocarbon core, lazabemide can inhibit the propagation of free radicals by electron-donating and resonance-stabilization mechanisms. These findings indicate that lazabemide is a potent and concentration-dependent inhibitor of membrane oxy-radical damage as a result of inhibiting membrane lipid peroxidation, independent of MAO-B interactions.     

N-propargylbenzylamine, a major metabolite of pargyline, is a potent inhibitor of monoamine oxidase type B in rats in vivo: a comparison with deprenyl.

In an effort to explore the contribution of the metabolites of pargyline towards the in vivo inhibition of monoamine oxidase (MAO), the effects of pargyline and its major metabolites on the production and metabolism of a number of biogenic amines were studied in rats. The administration of pargyline gave rise to three major ethyl acetate extractable metabolites: benzylamine, N-methylbenzylamine and N-propargylbenzylamine (NPB). Only NPB demonstrated in vivo monoamine oxidase inhibitory properties at an acute dose of 30 mg kg-1. The acute effects of pargyline, NPB, and deprenyl on urine and brain concentrations of a number of biogenic amines (phenylethylamine (PEA), m- and p-tyramine, noradrenaline (NA), dopamine, and 5-hydroxytryptamine (5-HT) and their metabolites were evaluated. Increased urine and brain concentrations of PEA were considered to represent in vivo inhibition of type B MAO while decreased concentrations of NA and 5-HT metabolites were regarded as indicators of an in vivo inhibition of MAO type A. NPB, like deprenyl and pargyline, significantly increased urine and brain PEA while only pargyline reduced 5-HT metabolism, suggesting that the metabolism of pargyline to NPB may contribute towards the MAO type B inhibitory effects of pargyline in vivo. Since the therapeutic benefits of MAO inhibitors in clinical practice usually require some period of chronic treatment, the chronic effects of repeated 14 daily doses of the above MAO inhibitors on central and peripheral biogenic amines were evaluated at the following times: during treatment, one day and five days after termination of treatment. The biochemical changes observed during the course of chronic NPB, pargyline and deprenyl treatments generally follow the expected in vitro characteristics of these drugs, but the detailed changes observed suggest clear differences. For example, the in vivo effect of pargyline on urine 5-hydroxyindoleacetic acid excretion was considerably weaker than its effect on the excretion of NA and dopamine metabolites. These changes are opposite to the in vitro effects of pargyline on 5-HT, dopamine and NA oxidative deamination. Inhibitions of the metabolism of all the amines studied were clearly observed during chronic MAOI treatments, but these effects were less evident five days after the end of treatment, suggesting an almost normal metabolism of biogenic amines. It is concluded that while MAO inhibitors may be the primary compound responsible for MAO inhibition, the effects of their metabolites in some cases may also play equally important roles in the regulation of monoamines both in the periphery and the brain.(ABSTRACT TRUNCATED AT 400 WORDS)     

Metabolism of selegiline hydrochloride, a selective monoamine b-type inhibitor, in human liver microsomes

The participation of cytochrome P-450 (CYP) isoforms in the metabolism of selegiline was investigated. Experiments using recombinant CYP isoforms expressed in human lymphoblastoid cells showed CYP2B6 to be the major CYP isoform involved with the metabolism of selegiline. CYP1A2 and CYP3A4 also contributed to the metabolism of selegiline but their catalytic activities were much less than that of CYP2B6. CYP2B6 had a higher affinity for both N-depropagylation (K(m)=21.4 microM) and N-demethylation (K(m)=25.2 microM) of selegiline than CYP3A4 and CYP1A2. In immunoinhibition studies using mixed human hepatic microsomes, selegiline N-depropagylation activity was most strongly inhibited by anti-CYP2B and anti-CYP3A antibodies, while selegiline N-demethylation activity was most inhibited by anti-CYP2B antibody. In CYP2B6-rich human hepatic microsomes, anti-CYP2B antibody had the strongest inhibitory effects on both activities. Selegiline inhibited CYP2B6-mediated (S)-mephenytoin N-demethylation activity and CYP2C19-mediated (S)-mephenytoin 4'-hydroxylation activity. These findings suggest that attention should be paid to the drug-drug interaction associated with CYP2B6 and CYP2C19. In conclusion, CYP2B6 participates in the metabolism of selegiline but the degree of its contribution varies with the level of its expression in human liver.     

CGS 9343B, a novel, potent, and selective inhibitor of calmodulin activity

1,3-Dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]- benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-o ne (1:1) maleate was synthesized in six steps from methyl anthranilate and designated CGS 9343B. CGS 9343B inhibited calmodulin-stimulated cAMP phosphodiesterase activity with an IC50 value of 3.3 microM. CGS 9343B was 3.8 times more potent than trifluoperazine (IC50 = 12.7 microM) as an inhibitor of calmodulin activity. CGS 9343B did not inhibit protein kinase C activity at concentrations up to 100 microM, whereas trifluoperazine inhibited protein kinase C activity with an IC50 value of 43.9 microM. CGS 9343B weakly displaced [3H]spiperone from postsynaptic dopamine receptors with an IC50 value of 4.8 microM while the value for trifluoperazine, a potent antipsychotic agent, was 0.018 microM. It is concluded that CGS 9343B is a novel, potent, and selective inhibitor of calmodulin activity. Unlike trifluoperazine, CGS 9343B does not inhibit protein kinase C activity and does not possess potential antidopaminergic activity.     

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     

The effect of deprenyl,a selective monoamine oxidase B inhibitor,on sleep and mood in man

The effect of (-)-deprenyl, a rapidly acting selective monoamine oxidase (MAO) B inhibitor, on the sleep and mood of six healthy young male adults was investigated. The drug was administered double-blind in a balanced cross-over design. The dose (5–10 mg/day for 3 days) was chosen to cause complete inhibition of MAO, a process which usually takes 1–2 weeks with conventional MAO inhibitors. The inhibition was monitored by measuring platelet MAO activity and phenylethylamine excretion. Urinary phenylethylamine concentration was raised in all subjects. Subjects were unaware of any sleep disturbance due to the drug although the electroencephalogram (EEG) showed increased wakefulness. The onset of rapid-eye-movement (REM) sleep was delayed and the total amount reduced; the amount of stage 2 sleep was increased. The only effect of the drug on mood was to decrease the level of alertness prior to sleep. There was a slight but significant increase in the pre-sleep systolic blood pressure. There were no effects due to drug withdrawal.     

Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse

The potential neuroprotective effects of rasagiline, N-propargyl-1R-aminoindan, a selective monoamine oxidase-B inhibitor and its inactive enantiomer TVP 1022, N-propargyl-1S-aminoindan were assessed against the sequelae of closed head injury in the mouse. Injury was induced in the left hemisphere under ether anaesthesia. Rasagiline (0.2 and 1 mg/kg) or TVP1022 (1 and 2 mg/kg) injected 5 min after injury accelerated the recovery of motor function and spatial memory and reduced the cerebral oedema by about 40-50%, (P < 0.01). The neuroprotective effects on motor function and spatial memory, but not on cerebral oedema, were prevented by scopolamine (0.2 mg/kg). Daily injection of rasagiline (1 mg/kg) from day 3 after injury accelerated the recovery of spatial memory but not motor function. Conclusions: Early administration of rasagiline or TVP1022 can reduce the immediate sequelae of brain injury. The mechanism of action does not appear to involve monoamine oxidase-B inhibition but could be mediated by the maintenance of cholinergic transmission in brain neurons.     

Mixed linear and non-linear disposition of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. Single oral doses (100-300 mg) and multiple oral doses (100-350 mg 12 hourly for 7 days) of lazabemide were administered to 35 young and 40 elderly healthy subjects. Plasma concentrations of unchanged drug were determined to study the dose-concentration relationship. 2. The elimination phase time course of lazabemide concentrations indicated concentration-dependent elimination after both single and multiple dosing. Nevertheless, maximum concentrations and areas under concentration-time curves increased almost proportionally with dose and accumulation after chronic dosing was less than a factor of 2; steady-state concentrations were achieved by the third day of dosing. The apparent half-life determining accumulation was approximately 8-9 h. 3. Drug absorption commenced rapidly after a dose; two components to the absorption process were detectable in young subjects possibly due to simultaneous administration of multiple tablets at the higher doses. 4. Observations after single and multiple dosing were described with a compartmental model allowing for parallel saturable (population mean +/- s.d.: maximum elimination rate Vmax/F: 2.8 +/- 1.4 mg h-1; concentration at half-maximum elimination Km: 36 +/- 19 micrograms l-1) and first-order (CL/F 16 +/- 3.8 l h-1) elimination pathways. No important difference between the young and the elderly subjects was noted in absorption or disposition parameters of lazabemide.     

Synthesis and study of a series of 3-arylcoumarins as potent and selective monoamine oxidase B inhibitors

New series of 6-substituted-3-arylcoumarins displaying several alkyl, hydroxyl, halogen, and alkoxy groups in the two benzene rings have been designed, synthesized, and evaluated in vitro as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Most of the studied compounds showed a high affinity and selectivity to the hMAO-B isoenzyme, with IC(50) values on nanomolar and picomolar range. Ten of the 22 described compounds displayed higher MAO-B inhibitory activity and selectivity than selegiline. Coumarin 7 is the most active compound of this series, being 64 times more active than selegiline and also showing the highest hMAO-B specificity. In addition, docking experiments were carried out on hMAO-A and h-MAO-B structures. This study provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of this 3-arylcoumarin scaffold.     

The neuropharmacological profile of N-methyl-N-propargyl-2-aminotetralin: a potent monoamine oxidase inhibitor

Summary N-methyl-N-propargyl-2-aminotetralin (N-0425), a semi rigid analogue of deprenyl was found to be a potent inhibitor of monoamine oxidase type-A and-B. The MAO inhibitory potency was determined in in-vitro, ex-vivo and in-vivo experiments for racemic N-0425 and for both enantiomers, and compared with deprenyl. Racemic N-0425 and (–)N-0425 were found to inactivate both MAO-A and-B to about the same extent in rat brain homogenates, whereas (+)N-0425 was 10 times more potent in inhibiting MAO-B than MAO-A under in-vitro conditions. The latter compound was almost 3 times less active than (–)deprenyl with respect to inactivation of MAO-B. In ex-vivo experiments it was shown that (±)- and (+)N-0425 inhibited rat striatal MAO-B activity almost completely 2 h after a dose of 0.01 mmol/kg ip, whereas both compounds produced a much less rapid inactivation of type-A MAO, which was about 65% after 23 h. No potentiation of the tyramine induced increase in systolic blood pressure was found in normotensive rats following doses up to 0.01 mmol/kg ip of racemic N-0425, but a potentiation was observed after a higher dose of 0.04 mmol/kg. Levels of dopamine and noradrenaline were both increased in rat frontal cortex after the administration of N-0425, which can be interpreted as a reflection of MAO inactivation. Since we were able to select a dose of (±)N-0425 which potently inhibits MAO, without producing a concomittant potentiation of the tyramine effect on blood pressure in normotensive rats, it is reasonable to suggest that this compound, like deprenyl, could be useful in the treatment of Parkinson's disease.Abbreviations used MAO monoamine oxidase - l-DOPA 3,4-dihydroxyphenylalamine - DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - 3-MT 3-methoxytyramine - NA noradrenaline - NM normetanephrine - 5-HT 5-hydroxytryptamine - 5-HIAA 5-hydroxyindoleacetic acid - PEA -phenylethylamine - N-0425 N-methyl-N-propargyl-2-aminotetralin Some of these results have been presented in a preliminary form at the 5th International Catecholamine Symposium, Göteborg, Sweden, June 12–16, 1983. This work was partly supported by a grant from Nelson Research, Irvine, California, USA     

Amethocaine-induced inhibition of mitochondrial monoamine oxidase activity

Amethocaine (tetracaine) (1-10 microM) produces a concentration-dependent in-vitro inhibition of mitochondrial membrane-bound MAO activity towards tyramine (18-84% in brain and 19-84% in liver) and 5-hydroxytryptamine (5-HT) (23-94% in brain and 20-100% in liver). At relatively higher concentrations (25-300 microM) of amethocaine, benzylamine oxidation is inhibited in brain (24-91%) and liver (29-100%). The extent of MAO inhibition is appreciably reduced when preincubation time of the enzyme with a low concentration (7.5 microM) of amethocaine is increased from zero to 45 min. This inhibition is reversible. The Km of MAO for tyramine is increased in brain (106-473%) and liver (121-352%) in the presence of amethocaine (2-7.5 microM) accompanied by a decrease in Vmax (21-51% in brain and 18-57% in liver). Similarly the Km of MAO for 5-HT is increased to the extent of 79-336% in brain and 51-225% in liver and the corresponding Vmax is decreased by 35-55% and 39-74%, respectively, in the presence of 2-5 microM amethocaine. At relatively higher concentrations (25-100 microM), amethocaine increases the Km of MAO for benzylamine in brain (25-101%) and liver (26-85%) and decreases the Vmax by 28-64% and 32-63% in the respective tissues. Thus these results suggest that amethocaine preferentially inhibits MAO-A and the nature of inhibition is reversible and of mixed type.     

p-Methoxyamphetamine,a potent reversible inhibitor of type-A monoamine oxidase in vitro and in vivo

p-Methoxyamphetamine is over 20 times as potent as (+)-amphetamine as an inhibitor of 5-HT oxidation by monoamine oxidase in mouse brain in vitro, with a K_i value of 0·22 μM. It is highly selective towards A-type monoamine oxidase and possesses only weak activity against the B-type enzyme (Ki value about 500 μM with benzylamine as substrate and solubilized rat liver mitochondria as enzyme source). It is 10 times more active than (+)-amphetamine in protecting mouse brain monoamine oxidase from inhibition by phenelzine in vivo. o-Methoxy- and m-methoxyamphetamines inhibit monoamine oxidase both in vitro and in vivo with potencies comparable with, or less than that of (+)-amphetamine.