Moclobemide antidepressant

In terms of the new MAO inhibitors that may become available in the future, it is possible that some new RIMAs may be approved as antidepressants. Moclobemide, available in many countries, is unlikely, for commercial reasons, to become available in the United States. Another promising RIMA, brofaramine, is also unlikely to be developed for any country. However, befloxatone is progressing in clinical trials, and other RIMAs are also potential drug development candidates, including RS-8359, cimoxatone, and toloxatone. 

Table 1 lists the MAO inhibitors that are already available or under investigation. These compounds fall into different chemical categories, including compounds that have the following properties antidepressant (moclobemide), antihypertensive (pargyline), antineoplastic (procarbazine), and antimicrobial (furazolidone). 

Monoamine oxidase inhibitor (MAOI) antidepressants have been in use for nearly 40 years. At the present time, they are viewed as second- or third-line antidepressant medications for reasons of both efficacy and safety. The available MAOIs are phenelzine sulfate (Nardil), isocarboxazid (Marplan), and tranylcypromine sulfate (Parnate). Two additional MAOI antidepressants, moclobemide and brofaromine, are approved for use in Europe and/or Canada. 

ANTICANCER AND IMMUNO-MODULATING DRUGS - cyclophosphamide 4. ANTICOAGULANTS-warfarin 5. ANTIDEPRESSANTS-moclobemide 6. ANTIEPILEPTICS-phenobarbitone, primidone... 

Given this retrosynthetic analysis, propose a synthesis for the antidepressant moclobemide. 

Reversible Inhibitors of Monoamine Oxidase. Selective MAO-A inhibitors, which aie leveisible (so-called RIMAs), have also been developed, theiefoie substantially leduciag the potential foi food and dmg iateiactions. Indeed, the tyiamine-potentiating effects of these dmgs is much reduced compared with the irreversible MAO inhibitors. The RIMAs represent effective and safer alternatives to the older MAO inhibitors. The only marketed RIMAs ate toloxatone [29218-27-7] and moclobemide (55). The latter is used widely as an effective, weU-tolerated antidepressant. 

Yet another nontricyclic antidepressant consists of a relatively simple morpholine derivative. Acylation of aziridine with p-chlorobenzoyl chloride gives the amide 130. This intermediate is. sufficiently reactive to undergo ring opening on treatment with morpholine. The product is the antidepressant agent moclobemide (131) 33J. 

Because of their lack of selectivity and their irreversible inhibition of MAO, the first MAOIs to be developed presented a high risk of adverse interactions with dietary tyramine (see Chapter 20). However, more recently, drugs which are selective for and, more importantly, reversible inhibitors of MAO-A (RIMAs) have been developed (e.g. moclobemide). These drugs are proving to be highly effective antidepressants which avoid the need for a tyramine-free diet. 

The discovery that MAO has two isoenzymes with different distributions, substrate specificity and inhibitor sensitivity has helped to rehabilitate the MAOIs to some extent. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. Whereas noradrenaline and 5-HT are metabolised preferentially by MAOa, tyramine and dopamine can be metabolised by either isoenzyme. Selective inhibitors of MAOa (e-g- moclobemide Da Prada et al. 1989) should therefore be safe and effective antidepressants whereas the selective MAOb inhibitor, selegiline, should not have any appreciable antidepressant activity (Table 20.5). 

In addition to this serious diet-drug interaction, irreversible MAOIs also potentiate the effects of sympathomimetic drugs like ephedrine found in over-the-counter cold remedies and recreational stimulants like amphetamine. The MAOIs also interact with drugs that increase synaptic concentrations of 5-HT, such as the tricyclic antidepressant clomipramine and the herbal SSRI antidepressant St John s wort (Hypericum spp.). The resulting serotonin syndrome is characterised by hyperthermia and muscle rigidity. While devoid of these side effects the reversible MAO-A inhibitor moclobemide has yet to establish itself as a first-line alternative to the SSRIs. 

Monoamine Oxidase inhibitors (MAOis). There are no controlled studies of MAOIs for the treatment of AN. In addition, the dietary restrictions imposed on patients taking this class of antidepressant and their propensity for lowering blood pressure makes their use in AN inadvisable. In the future, the issue of using MAOis may be reopened with the advent of the so-called reversible MAOis such as moclobemide that apparently do not require a tyramine-restricted diet. 

Antidepressants amitriptyline, clomipramine, imipramine, moclobemide, citalopram Antipsychotics olanzapine... 

Antidepressants of this class, such as moclobemide, have a high selectivity and affinity for MAO-A. Flowever, unlike the MAOIs, the RIMAs are reversible inhibitors of the enzyme and can easily be displaced from the enzyme surface by any primary amine which may be present in the diet. This means that the dietary amines are metabolized by MAO in the wall of the gastrointestinal tract while the enzyme in the brain and elsewhere remains inhibited. Thus the RIMAs have brought the MAOIs back into use as antidepressants in general practice. It is now evident that the RIMAs are not as potent as most currently available antidepressants. 

Bromocriptine is a dopamine agonist acting by direct stimulation of the dopamine receptors. In Parkinson s disease, it is reserved for use in patients who are intolerant to levodopa or in whom levodopa alone is not sufficient. Orphenadrine is an antimuscarinic indicated in Parkinson s disease. Antimuscarinics tend to be more effective than levodopa in targeting tremor rather than rigidity and bradykinesia. Moclobemide is an antidepressant referred to as a reversible monoamine oxidase inhibitor (RIAAA) type A. 

Lorazepam is a short-acting benzodiazepine indicated for use in relieving anxiety and insomnia. Lorazepam may also be administered perioperatively to alleviate pain and in status epilepticus. Imipramine is a tricyclic antidepressant, paroxetine is a selective serotonin re-uptake inhibitor, venlafaxine is a serotonin and adrenaline re-uptake inhibitor and moclobemide is a reversible monoamine oxidase inhibitor. Imipramine, paroxetine, venlafaxine and moclobemide are all classified as antidepressants. 

These mediators probably play significant roles in CNS functions consistent with the stimulant effects of MAO inhibitors on mood and psychomotor drive and their use as antidepressants in the treatment of depression (A). Tranylcypromine is used to treat particular forms of depressive illness as a covalently bound suicide substrate, it causes long-lasting inhibition of both MAO isozymes, (MAOa, MAOb). Moclobemide reversibly inhibits MAOa and is also used as an antidepressant. The MAOb inhibitor selegiline (deprenyl) retards the cat-obolism of dopamine, an effect used in the treatment of parkinsonism (p. 188). 

Dmg-induced serotonin syndrome is generally mild and resolves when the offending drugs are stopped. However, it can be severe and deaths have occurred. A large number of drugs have been implicated including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), pethidine, lithium, and dextromethorphan. The most severe type of reaction has occurred with the combination of selective serotonin re-uptake inhibitors and monoamine oxidase inhibitors. Both non-selective MAOIs such as phenelzine and selective MAOIs such as moclobemide and selegiline have been implicated. 

Therapeutic efficacy by selective MAO-A inhibitors (such as clorgyline or moclobemide) in major depressions strongly suggests that MAO inhibition at central serotonin or norepinephrine synapses or both is responsible for the antidepressant properties of these agents. However, since complete MAO-A inhibition is achieved clinically within a few days of treatment, while the antidepressant effects of these drugs are not observed for 2 to 3 weeks, suggests that additional actions must be involved. 

Goldberg R. Antidepressant use in the elderly. Current status of nefazodone, venlafaxine and moclobemide. Drugs Aging 1997,11 119-131. 

The side effects of antidepressants, sometimes very unpleasant, olten lead patients to interrupt their treatment or to reduce the drug dose, which involves a great risk in view of the high relapse rate and danger of suicide in depression. The newer antidepressants, such as trazodone, fluoxetine and other SSRIs and moclobemide, are characterized by better tolerability and lower toxicity and are therefore preferred in the treatment of outpatients and elderly patients (Rudorfer and Potter, 1989). A detailed list of general and specific common side effects associated with the newer generation of antidepressants is seen in Table 1.7. 

Reports are on hand relating to more recent antidepressants such as bupropion, citalopram (Fairweather ei ul., 1997), fluoxetine (Gelfin et ul.. 1998). moclobemide (Dingemanse et ul., 1998) and paroxetine (Brauer et ul.. 1995). These products, in agreement with their clinical profiles, produce fewer subjective effects and generally less sedation in healthy subjects than the older... 

Area of assessment Clinically sedative antidepressants, e.g. amitriptyline, mianserin, trimipramine Less sedative antidepressants, e.g. bupropion, fluoxetin, moclobemide, nefazodone ... 

Results of crossover studies indicate that lithium is efficacious in treating acute depression in bipolar subjects unequivocally (36%, 29/80) and partially (43%. 34/80). respectively (Xomberg and Pope, 1993 Keck and McElroy, 2002). Various antidepressants have shown variable rates of efficacy in the treatment of acute bipolar depression, i.e. desipramine (50%), maprotiline (67%), imipra-mine (40 60%), tranylcypromine (87%), moclobemide (53%) and fluoxetine (60%) (Keck and McElroy, 2002). Among the anticonvulsants, valproic add and lamotrigine appear to have some potential efficacy in the treatment of acute bipolar depression (Calabrese et al., 1992, 1999 Fatemi et al., 1997). 

MAOis are usually not recommended because of uncertainty about adherence to dietary restrictions and the very real problem of hypotension. When used in selected patients, however, phenelzine has been found to be safe and effective. As noted in Chapter 7, however, the eventual introduction of selective, reversible MAOIs, such as moclobemide, may lead to a greater use of this class of antidepressants in all age groups. 

A number of antidepressant drugs, particularly SSRIs, can increase plasma prolactin concentrations, although galactorrhea is uncommon. In a prescription event monitoring survey of about 65 000 patients, compared with SSRIs, moclobemide was associated with a relative risk of galactorrhea of 6.7 (95% Cl = 2.7, 15) (727). However, this was substantially less than the risk associated with the dopamine receptor antagonist risperidone (relative risk compared with SSRIs 32 95% Cl = 14, 70). 

Nevertheless, the data suggest that moclobemide may be more likely to cause galactorrhea than other antidepressant drugs. 

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