4- 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. 

C14H14CI2N2O2 16390-18-4) see Indometacin 4-chlorobenzoic acid methyl ester (C8H7CIO2 1126-46-1) see Moclobemide 2-chlorobenzoic add potassium salt (C7H4CIICO2 16463-38-0) see Thiethylperazine... 

C7H4CI2O 122-01-0) see Acemetacin Benoxaprofen Bezafibrate Feclobuzone Fenofibrate Indometacin Moclobemide Progabide Rebamipide Zomepirac (2-chlorobenzoyi)cyciopentane (C12H13CIO 6740-85-8) see Ketamine... 

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. 

RIMA Reversible, selective inhibition of MAO (causes Moclobemide ... 

Figure 20.2 The chemical structure of some well-known MAO inhibitors. Most of these drugs irreversibly inhibit both MAOa and MAOb but reversible inhibitors (RIMAs), such as moclobemide, inhibit MAOa only...

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). 

Both these predictions are borne out by clinical experience despite the snag that only MAOb is found in serotonergic neurons (Saura et al. 1996). So far, there is no explanation for this anomaly. However, the lack of a tyramine-induced pressor effect with moclobemide probably owes more to the fact that it acts as a reversible inhibitor of MAOa (RIMA) than to its isoenzyme selectivity. Its reversible inhibition of MAOa means that, should tyramine ever accumulate in the periphery, it will displace... 

Reversible ( RIMA ) Befloxaton Brofaromine Moclobemide Pirlindole Toloxatone ... 

Da Prada, M, Kettler, R, Keller, HH, Burkard, WP, Muggli-Maniglio, D and Haefely, WE (1989) Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. /. Pharmacol. Exp. Ther. 248 400-414. 

Isocarboxizid, phenelzine, selegiline, tranylcypromine, moclobemide, clorgiline, and linezolid... 

CYP2D6 TCAs, SSRIs, haloperidol, mirtazepine, zuclopenthoxil, venlafaxine, sertraline CYP2C19 TCAs, mephenytoin, diazepam, moclobemid, venlafaxine... 

Maprotiline, Moclobemide, Mianserin, Fluoxetine (Prozac), Paroxetine, Sertraline, Fluvoxamine, Citalopram, Venlafaxin (generic IR formulation and the brand Venlafaxine XR), Mirtazapine, Flupentixol-melitracen (Deanxit), Tianeptine, Extract of St. John s Wort, Buspirone Depression and anxiety... 

Berlin, I.S.S., Spreux-Varoquaux, O., Launay, J.M., Olivares, R., Millet, V., Lecrubier, Y., Puech, A.J. A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clin. Pharmacol. Ther. 58 444, 1995. 

Inside the cytoplasm of the presynaptic neuron the monoamines are exposed to the mitochondrial outer membrane-bound enzyme monoamine oxidase (MAO). MAO breaks the monoamines down into inactive metabolites before they are taken up into the vesicles. However, if MAO is inhibited, then the monoamines enter the vesicles and are available for release. MAO inhibitors, such as moclobemide, have been used in the treatment of depression, since they increase the availability of noradrenaline and serotonin. Selegiline is used for Parkinson s disease, since it raises dopamine levels. 

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. 

Larsen, J. K., Gjerris, A., Holm, P. etal. Moclobemide in depression a randomized, multicentre trial against isocar-boxazide and clomipramine emphasizing atypical depression. Acta Psychiatr. Scand. 84 564-570,1991. 

MAOls Brofaromine Isocarboxizide Moclobemide Phenelzine Tranylcypromine... 

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