Description

Moclobemide is the first of a new generation of non-hydrazine, reversible MAO-A inhibitors useful in the treatment of depression. Moclobemide is a selective inhibitor of MAO-A, allowing tyramine to be metabolized by MAO-B. In controlled studies, moclobemide was clinically superior to desipramine and showed no cholinergic or cardiovascular side-effects. A metabolite is currently under investigation for treatment of Parkinson’s disease,.

Description

Moclobemide (Item No. 24361) is an analytical reference standard categorized as an antidepressant. This product is intended for research and forensic applications.

Chemical Properties

White to Off-White Solid

Originator

Hoffmann-LaRoche (Switzerland)

Uses

A reversible monoamine oxidase inhibitor.

Uses

Antidepressant;Mono amine oxidase inhibitor (Type A)

Definition

ChEBI: A member of the class of benzamides that is benzamide substituted by a chloro group at position 4 and a 2-(morpholin-4-yl)ethyl group at the nitrogen atom. It acts as a reversible monoamine oxidase inhibitor and is used in the treatment of depression.

brand name

Aurorix

Biochem/physiol Actions

Moclobemide is a reversible monoamine oxidase A inhibitor (MAOI); antidepressant. Elimination half-life in humans = 1 -3 hrs; absolute oral bioavailability. Unlike other MAO inhibitors, does not significantly increase blood pressure in humans upon combination with tyramine.

Mechanism of action

Moclobemide is an RIMA that preferentially inhibits MAO-A (~80%) and, to a lesser extent, MAO-B (20–30% inhibition), thereby increasing the concentration of 5-HT, NE, and other catecholamines in the synaptic cleft and in storage sites. During chronic therapy with the MAOIs, adaptive changes at the noradrenergic and serotonergic receptors occur (“downregulation”) as a result of neurotransmitter hypersensitivity because of prolonged concentrations of NE and 5-HT at the postsynaptic receptor. This mechanism is likely the basis for its antidepressant activity. Inhibition of MAO-A by moclobemide is short-acting (maximum, 24 hours) and reversible. This is in contrast to phenelzine, which is nonselective, long-acting, and irreversible in its binding to MAO-A and MAO-B.
The pharmacokinetics for moclobemide are linear only up to 200 mg; at higher doses, nonlinear pharmacokinetics are observed. Although well absorbed from the GI tract, the presence of food reduces the rate but not the extent of absorption of moclobemide. Small quantities of moclobemide are distributed into human breast milk. Moclobemide undergoes a complex metabolism, initially involving morpholine carbon and nitrogen oxidation, deamination, and aromatic hydroxylation. The N-oxide and ring-opened metabolites retain some in vitro MAO-A inhibition. Moclobemide is a weak inhibitor of CYP2D6 in vitro. It is extensively metabolized in the liver by oxidation and is eliminated primarily into the urine as conjugates. Less than 1% of an administered dose of moclobemide is eliminated unmetabolized.
Because moclobemide is partially metabolized by the polymorphic isozymes CYP2C19 and CYP2D6, plasma concentrations of moclobenmide may be affected in patients who are poor metabolizers. In patients who are slow metabolizers, the AUC for moclobemide was 1.5 times greater than the AUC in patients who are extensive metabolizers and receiving the same dose. This increase is within the normal range of variation (up to twofold) typically seen in patients.

Clinical Use

Reversible MAOI:
Depression
Social phobia

Synthesis

(1) Synthesis of bromoethylamine hydrobromide

At -5-0, 40% hydrobromic acid was added to the raw material ethanolamine, m hydrobromic acidm ethanolamine=51, stirring, and the temperature of the system was controlled not to exceed 0. After the dropwise addition, the reaction was continued with stirring for 0.5 h. At the end of the reaction, white needle-like crystals were obtained after distillation under reduced pressure, and the melting point of the product was 70-71C. The reaction was continued with dropwise addition of hydrobromic acid in the reaction system. In the reaction system continue to add the same amount of 40% hydrobromic acid dropwise, to be added after the dropwise completion, add 100-150 ml of solvent xylene, temperature reflux reaction 20-24h, the reaction temperature of 120-128 C, decompression distillation of the solvent, pour out the product while it is still hot, washed with cyclohexanone two times, to get the white crystalline product of 2-Bromoethylamine Hydrobromide, the melting point of 168-170 C. The reaction is completed by stirring for 0.5 h. After distillation under reduced pressure, get white needle-like crystal, the melting point is 168-170 C.

(2) Synthesis of 4-chloro-N-(2-bromoethyl)benzamide

5 times the amount (m:v) of water was added to 2-bromoethylamine hydrobromide and dissolved with stirring. An equimolar amount of p-chlorobenzoyl chloride and 10% NaOH solution with 2-bromoethylamine hydrobromide was added dropwise at -5 C. After dropwise addition, the reaction was stirred at low temperature for 1 h. Filtering and washing with water gave 4-chloro-N-(2-bromoethyl)benzamide as a white solid.

(3) Synthesis of moclobemide

4-chloro-(2-bromoethyl)benzamide add 7 times the molar amount of morpholine, stirring reflux, the temperature is 123-125 , the reaction of 10-12h after the cooling down, add water and 5% NaOH solution to adjust the pH value of 11, filtration and water washing, petroleum ether twice recrystallization, get white solid morpholino chlorobetaine, the melting point of 137.5 ~ 138.5 , the content is 99.60%.

Drug interactions

Drug interactions for the RIMAs include interaction with SSRI antidepressants, which can cause the 5-HT syndrome. The effect of stimulant drugs, such as methylphenidate and dextroamphetamine (used to treat ADHD), may be increased. Some over-the-counter cold and hay fever decongestants (i.e., sympathomimetic amines) can have increased stimulant effects. Selegiline, a selective MAO-B used for Parkinson's disease, should not be used concurrently with the RIMAs. Unlike the irreversible MAOIs, no significant interactions with foods occur, because the selective inhibition of MAO-A does not stop the metabolism of tyramine. The RIMAs must not be taken concurrently with a nonreversible MAOI.

Metabolism

Moclobemide is extensively metabolised in the liver, partly by the cytochrome P450 isoenzymes CYP2C19 and CYP2D6. Metabolites of moclobemide and a small amount of unchanged drug are excreted in the urine

storage

Room temperature

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.