Monoamine oxidase irreversible

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

Monoamine—Oxidase Inhibitors. In the mid-1950s, tuberculosis patients with depression being treated with iproniazid (42) were occasionally reported to become euphoric. This observation led to the discovery of irreversible monoamine—oxidase (MAO) inhibiting properties. Hydrazine and nonhydrazine-related MAO inhibitors were subsequentiy shown to be antidepressants (122). Three other clinically effective irreversible MAO inhibitors have been approved for treatment of major depression phenelzine (43), isocarboxazid (44), and tranylcypromine (45). 

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. 

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

A method has been described by which the effects of reversible competitive monoamine oxidase inhibitors might be estimated successfully ex vivo (Green, 1984). This method relies upon the ability of a reversible competitive inhibitor (perhaps administered chronically) to protect against the effects of an irreversible inhibitor (administered as a single dose) that binds to the enzyme active site. As inhibition by an irreversible inhibitor can be measured quite easily ex vivo, the degree of irreversible inhibition in an animal coadministered a reversible competitive inhibitor would be less than that in a control animal that received only the irreversible inhibitor. The difference would provide an estimate of the degree to which enzyme was bound (protected) by the reversible inhibitor in vivo. 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

All the commonly used MAOIs (monoamine oxidase inhibitors), exemplified by phenelzine, isocarboxazid and pargyline, are irreversible inhibitors of both forms of the enzyme, forming covalent bonds with the active sites... 

The N-benzyl-l-methylcyclopropylamine 7 is an irreversible inhibitor of the mitochondrial flavoenzyme monoamine oxidase (MAO). It was suggested that... 

Serious toxic reactions with delirium can arise when specific serotonin reuptake inhibitors (SSRIs) are taken with other drugs that increase central and peripheral serotonergic activity. Known as the serotonin syndrome , this reaction consists of excitation, restlessness, fluctuations in consciousness, with tremor, rigidity, myoclonus, sweating, flushing, pyrexia, cardiovascular changes, and rarely coma and death (Sternbach, 1991). The syndrome has occurred when SSRIs have been combined with irreversible monoamine oxidase... 

Examples of monoamine oxidase inhibitors are phenelzine, tranylcypromine, isocarboxazid and mo-clobemide. They are indicated for atypical depression. Changes in the neurotransmitter levels are seen in several days but the clinical effect may lag by several weeks. Phenelzine is a non-selective hydrazine-type monoamine oxidase inhibitor while the also non-selective inhibitor tranylcypromine is of the non-hydrazine-type. Phenelzine, tranylcypromine and isocarboxazid are irreversible inhibitors. Phenelzine is partly metabolized by acetylation and slow acetylators are more prone to toxicity. It has anxiolytic properties and superior efficiacy in treating severe anxiety. 

Selegiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) as long as it is... 

I.A. McDonald, J.M. Lacoste, P. Bey, M.G. Palfreyman, M. Zreika, Enzyme-activated irreversible inhibitors of monoamine oxidase Phenylallylamine stmcture-activity relationships, J. Med. Chem. 28 (1985) 186-193. 

R.W. Fuller, S.K. Hemrick-Luecke, B.B. Molloy, A/-[(2-o-lndophenoxy)ethyl]cyclopro-pylamine hydrochloride (LY121768), a potent and selective irreversible inhibitor of type A monoamine oxidase, Biochem. Pharmacol. 32 (1983) 1243-1249. 

Mechanism of Action An antiparkinson agent that irreversibly inhibits the activity of monoamine oxidase type B, the enzyme that breaks down dopamine, thereby increasing dopaminergic action. Therapeutic Effect Relieves signs and symptoms of Parkinson s disease. 

Nonselective and Irreversible Inhibitors of Monoamine Oxidase A and Monoamine Oxidase B... 

Monoamine oxidase inhibitors. The monoamine oxidase inhibitors (MAOIs) inhibit the intracellular catabolic enzyme monoamine oxidase. There are two types of monoamine oxidase MAO-A and MAO-B, both of which metabolize tyramine and dopamine. In addition, MAO-A preferentially metabolizes norepinephrine, epinephrine, and serotonin, and MAO-B preferentially metabolizes phenylethylamine (an endogenous amphetamine-like substance) and N-methylhistamine (Ernst, 1996). Some MAOIs are selective for A or B and some are nonselective (mixed). In addition, irreversible MAOIs (e.g., phenelzine, tranylcypromine) are more susceptible to the cheese effect than are the reversible agents (e.g., moclobemide). 

Another approach is to develop selective and reversible MAOIs. The goal again is to produce agents with a minimal risk of tyramine reactions and thus markedly diminish the need for the dietary restrictions that have plagued the use of nonselective and irreversible A, B inhibitors. Collaborative clinical trials of the reversible inhibitors of monoamine oxidase A (RIMAs) in Europe have included more than 2,000 patients, many hospitalized for more severe, endogenous depressive episodes (183). In comparison trials with the TCAs, the onset of effect with RIMAs was also more rapid in some cases. 

Thakore J, Dinan TG, Kelleher M. Alcohol-free beer and the irreversible monoamine oxidase inhibitors. Int Clin Psychopharmacol 1992 7 59-60. 

The enzyme, monoamine oxidase, exists in two forms MAO-A (intestinal mucosa and intraneuronally in the brain) and MAO-B (platelets and mainly extraneuronally in the brain). Serotonin is preferentially metabolised by MAO-A and noradrenaline (NA norepinephrine), and dopamine and lyramine by both forms. The first generation MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) inhibit both MAO-A and MAO-B and are thought to work by increasing the availability of 5-HT and NA in the synapse—with longer-term adaptive effects occurring as for the TCAs. These MAOls are irreversible, i.e. they permanently inactivate MAO. Thus, recovery of activity occurs slowly, over days, as new MAO molecules are synthesised. 

Monoamine oxidase inhibitors MAO is found in neural and other tissues, such as the gut and liver. In the neuron, this enzyme functions as a "safety valve" to oxidatively deaminate and inacti vate any excess neurotransmitter molecules (norepinephrine, dopamine, or serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors2 may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumu late within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs. 

In 1982 a number of young people in California injected themselves with an illegally manufactured opiate drug that was subsequently found contaminated with N-methyl-4-phenyltetrahydropyridine (MPTP). Within a few days they developed irreversible symptoms of Parkinson disease. Subsequent investigation revealed that MPTP itself is not toxic but that it is oxidized by monoamine oxidase B (MAO-B) to the corresponding pyridinium derivative MPP+ (Eq. 30-4). It is this pyridinium derivative, or perhaps... 

---