Moclobemide (Ro 111163)

Moclobemide is a reversible inhibitor of monoamine oxidase-A (MAO-A) with IC50 value of 10μM [1].

Moclobemide is a prototype of RIMA agents. It is found to possess antidepressant efficacy with less risk of fatal side-effects like hypertensive crisis. Moclobemide shows a weak but specific inhibition of MAO-A in the in vitro assay using rat brain homogenates. The IC50 values of MAO-A and MAO-B in the assay are 6mM and 1000mM, respectively. In ex vivo animal experiments, moclobemide produces an inhibition of 80% in the brain and liver. Additionally, the long-term administration of high doses of moclobemide is found to down-regulate β-adrenoceptors and increase the agonist binding affinity of α1-adrenoceptors. Moreover, moclobemide is rapidly and almost completely absorbed after oral administration. The bioavailability of moclobemide is about 50% after a single administration of 100 mg [2].

References:
[1] Pisani L, Barletta M, Soto-Otero R, Nicolotti O, Mendez-Alvarez E, Catto M, Introcaso A, Stefanachi A, Cellamare S, Altomare C, Carotti A. Discovery, biological evaluation, and structure-activity and -selectivity relationships of 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides, a novel class of potent and selective monoamine oxidase inhibitors. J Med Chem. 2013 Mar 28;56(6):2651-64.
[2] Nair NP, Ahmed SK, Kin NM. Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide. J Psychiatry Neurosci. 1993 Nov;18(5):214-25.

In vitro hepatic biotransformation of moclobemide (Ro 11-1163) in man and rat.[Pubmed:8259692]

Xenobiotica. 1993 Oct;23(10):1101-11.

1. Moclobemide, an inhibitor of monoamine oxidase, shows mixed MAO A/B inhibition in rat, but pure MAO A inhibition in man. This is attributed to a primary amine metabolite which inhibits MAO B in vitro, but which is not detected in human plasma in vivo. A secondary amine metabolite, also present in rat but not human plasma, inhibitors MAO B in vivo but not in vitro. 2. We have studied the biotransformation of moclobemide in vitro, to investigate whether hepatocytes and hepatic subcellular fractions can reproduce the in vivo interspecies differences. 3. Moclobemide was more extensively metabolized by rat liver preparations, compared with man. For example, of an initial 100 nmol, 78 and 25 nmol were metabolized within 24 h by rat and human hepatocytes in primary culture, respectively. 4. Substantial amounts of secondary amine (12.5 nmol) were found with the rat preparation, compared with low amounts (1.5 nmol) from human hepatocytes. Similarly, for the primary amine, 1.5 nmol were formed by the rat hepatocytes compared with trace amount in the human preparations. 5. Identities of the two amines were confirmed by h.p.l.c. cochromatography and negative CI GC-MS. 6. In conclusion, all the in vitro models, but particularly hepatocytes, reflected the metabolism of moclobemide in vivo. Consequently, liver preparations can be used prospectively to screen the selectivity of related development compounds.

Moclobemide (Ro 11-1163) versus tranylcypromine in the treatment of endogenous depression.[Pubmed:2248076]

Acta Psychiatr Scand Suppl. 1990;360:63.

In this study, moclobemide (100-350 mg daily) was compared with tranylcypromine (10-30 mg daily) in 40 patients with endogenous depression. Treatment was randomly allocated and most patients also received benzodiazepines or mild neuroleptics concomitantly. Improvement on the Hamilton Rating Scale for Depression at the end of treatment was 66% for moclobemide and 41% for tranylcypromine patients. There were 3 suspected tyramine reactions in patients on tranylcypromine. Tolerance was considered good or very good for 95% of moclobemide patients, and for 75% of tranylcypromine patients. No clinically relevant changes in laboratory data were attributed to either of the trial drugs. The results clearly favour moclobemide over tranylcypromine for both efficacy and tolerance in the treatment of endogenous depression.

Moclobemide (Ro 11-1163) safety in depressed patients.[Pubmed:2248078]

Acta Psychiatr Scand Suppl. 1990;360:69-70.

Safety aspects were compared in 2203 patients given moclobemide and 1214 who received other antidepressants or placebo. A total of 2294 adverse events were reported by patients on moclobemide, mainly subjective symptoms (28.6%). Adverse events such as dry mouth, tremor, sweating, dizziness and constipation occurred much more frequently among 681 patients treated with various tricyclic antidepressants than in the 694 moclobemide patients with whom they were compared. Among 271 placebo-treated patients there were 287 adverse events, compared with 386 events in the 285 moclobemide patients in the same studies. Hypertensive episodes or food-drug interactions were reported by 19 patients on moclobemide and 5 on other antidepressants, but in only 2 of the former was ingestion of cheese a possible cause of headache. The assessment of tolerance on moclobemide was essentially the same as for placebo. Of the 1401 moclobemide patients in the electronic database, only 3.2% stopped treatment prematurely because of poor tolerance; the rates were higher for tranylcypromine, nomifensine, desipramine, clomipramine, amitriptyline and imipramine. During treatment, 6 patients attempted suicide with moclobemide alone (950-2000 mg) or together with imipramine (300 mg and 1200 mg). None of the intoxications was life-threatening.

Controlled comparison of RO 11-1163 (moclobemide) and placebo in the treatment of depression.[Pubmed:1345409]

Acta Psychiatr Belg. 1992;92(6):355-69.

Moclobemide was compared to placebo in two parallel groups of depressed patients, in a multicenter randomized, double-blind study of six weeks treatment duration. Forty seven patients participated in the study: 23 received moclobemide (flexible dose 300-600 mg/day) and 24 placebo. They were evaluated weekly for efficacy and tolerability. Moclobemide was more efficacious than placebo as judged by analysis on the total score on the Hamilton depression scale (p < 0.05) and by the overall assessment of efficacy (p < 0.01). Moclobemide was also more effective than placebo in the subgroup with neurotic depression (p < 0.05). In addition, the number of patients prematurely terminating treatment for inefficacy, was higher in the placebo than in the moclobemide group (12 versus 2, p < 0.01). The number and the severity of side-effects tended to be slightly greater in the moclobemide than in the placebo group, but this did not reach a level of significance. Cardiovascular tolerability was good in both treatment groups. No hypertensive crisis was reported. Hematology, clinical chemistry and urine analysis were not affected by the treatment in any clinically significant fashion.

Pharmacological profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A.[Pubmed:2913284]

J Pharmacol Exp Ther. 1989 Jan;248(1):391-9.

The novel antidepressant moclobemide is a reversible inhibitor of monoamine oxidase (MAO), preferentially of type A. Moclomide was active in three animal models considered predictive for antidepressant activity: 1) it prevented dose-dependently akinesia and blepharospasm induced in mice and rats by Ro 4-1284, a short-acting amine releasing agent. Prevention of akinesia by moclobemide also depended upon the dose of Ro 4-1284. For comparison also, effects of cimoxatone, harmaline, tranylcypromine and clorgyline are presented: 2) in cats, it selectively and dose-dependently suppressed rapid eye movement sleep without disturbing the sleep-wakefulness cycle; and 3) in the behavioral despair test in mice, it decreased the immobility score to a similar degree as amitriptyline or imipramine. In addition, moclobemide potentiated 5-hydroxytryptophan-induced stereotypies in rats with a potency similar to cimoxatone and with a duration of action of less than 24 hr. Moclobemide had almost no effect on the spontaneous behavior in mice, rats, cats and monkeys. Only in higher doses, marginal sedation and slight impairment in motor performance were seen. Moclobemide did not prevent pilcarpine-induced salivation in mice, demonstrating the absence of anticholinergic activity. Blood pressure and heart rate of freely moving, spontaneously hypertensive rats were only slightly decreased for less than 3 hr. Moclobemide moderately potentiated the pressor effect of p.o. tyramine in rats. In conclusion, the reversible MAO inhibitor moclobemide is active in animal models sensitive to all major drugs used in the treatment of depression. In contrast to imipramine-like antidepressants, it lacks anticholinergic activity and it differs from classic MAO inhibitors by potentiating only weakly the pressor effect of p.o. tyramine.

Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A.[Pubmed:2783611]

J Pharmacol Exp Ther. 1989 Jan;248(1):400-14.

Moclobemide belongs to a new generation of short-acting, reversible, monoamine oxidase (MAO) inhibitors. In vitro (rat brain homogenates) moclobemide inhibits MAO-A selectively with lower potency than many of the reference MAO inhibitors. However, when measured ex vivo in the rat, the potency of moclobemide is similar to that of reference compounds. In vivo the drug induces a dose-dependent, short-lasting (8-16 hr) and preferential inhibition of MAO-A in the brain and both MAO-A and MAO-B inhibition in extracerebral organs (liver, small intestine and kidney). In the extracerebral tissues of the rat moclobemide induces marked peripheral MAO-B inhibition due to rapid and extensive biotransformation of its morpholine ring. The active molecular species is probably the metabolite Ro 16-6491. The moderate MAO-B inhibition measured after moclobemide intake in human platelets indicates that only minor amounts of Ro 16-6491 are formed in humans. Virtually all metabolites of moclobemide so far identified have been tested in vitro and ex vivo in the rat and proved to be either equipotent or, mostly, less effective than moclobemide as MAO-A inhibitors. In liver homogenates of moclobemide-treated rats MAO-A activity recovers during dialysis or simple incubation at 37 degrees C, suggesting a biodegradation of moclobemide and/or the moclobemide-derived active metabolite(s) by MAO itself or a slow dissociation of the active inhibitory species from the enzyme. Similar to other MAO-A inhibitors, moclobemide induces an increase in the rat brain levels of 5-hydroxytryptamine, norepinephrine and dopamine and a concomitant decrease of their deaminated metabolites. These effects are of short duration (8-16 hr) and parallel the time course of MAO-A inhibition. Moclobemide administered subchronically down-regulates beta adrenoceptors as shown by binding experiments with brain cortical membranes using dihydroalprenolol as ligand. In vitro MAO inhibition by moclobemide is specific in that the compound does not affect other amine oxidases or monoamine uptake mechanisms; furthermore, it does not interact with various neurotransmitter or drug receptor sites. In conclusion, a large body of preclinical evidence characterizes moclobemide as a short-acting and reversible MAO-inhibitor. The neurochemical profile of moclobemide indicates clearly that this nonhydrazine nonhepatotoxic MAO-A inhibitor represents a novel and safe drug for treatment of affective disorders.

Moclobemide(Ro111163) is a reversible monoamine oxidase inhibitor (MAOI) selective for isoform A (RIMA) used to treat major depressive disorder.

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