Monoamine oxidase inhibitors selective irreversible

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. 

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). 

Because of undesirable side effects associated with monoamine oxidase inhibitor therapy (see section 2.3.2), pharmaceutical companies nearly abandoned research on new analogs in the 1960s. The early MAO inhibitors were nonselective and irreversible. Today, efforts toward the development of monoamine oxidase inhibitors are focused on selective MAQA or MAOB inhibitors. Selective MAOB inhibitors are being examined in the treatment of, for example, schizophrenia, Alzheimer s disease, and Parkinson s disease. MAO-B inhibitors might be effective in the treatment of depression, but relatively little woik has been done in this area. Selegiline... 

Traditionally, dysthymic disorder has not been the focus of pharmacotherapeutic interventions, given its chronicity and the presumed non-biological personality variables associated with it. Psychotherapy and psychoanalysis were generally considered the first-choice treatment options, although these treatment modalities have not been well studied in controlled trials. However, as a result of a series of placebo-controlled medical trials, this attitude has been changed. Among the antidepressants found to be superior to placebo are the selective serotonin reuptake inhibitors (SSRIs, with results being evident so far with fluoxetine and sertraline), the tricyclic antidepressants (TCAs) amitriptyline, desipramine, and imipramine (with a 40-60% favorable response), and the reversible and irreversible monoamine oxidase inhibitors (MAOIs) moclobemide and phenelzine, respectively. 

Selective serotonin reuptake inhibitors (SSRIs) are the first-line therapy for PTSD. Efficacy for fluoxetine, paroxetine, and sertraline has been demonstrated in well-designed double-blind placebo-controlled studies to reduce all symptom domains (intrusive recollection, avoidance/numbness, and hyperarousal). - Other treatment options include the tricyclic antidepressants (TCAs) amitriptyline and imipramine and the irreversible monoamine oxidase inhibitor (MAOl) phenelzine, which have been shown to reduce re-experiencing. However, in comparison with SSRIs, TCAs and phenelzine are associated with a higher incidence of side-effects, risk of overdose, and poor compliance. Alprazolam has demonstrated anecdotal efficacy however, regular use of benzodiazepines is not recommended. Benzodiazepines can be used on an as-needed basis for specific symptoms (e.g. sleep disturbances). CBT has shown beneficial effects in relatively well-controlled studies, while the results with exposure therapy are... 

Selective serotonin reuptake inhibitors (SSRIs) are regarded as first-line treatment in social phobia. Fluvoxamine, paroxetine, and sertraline have been shown to be effective in double-blind placebo-controlled studies. - The irreversible monoamine oxidase inhibitor (MAOI) phenelzine shows robust results in terms of efficacy and has demonstrated (at least anecdotally), its efficacy in improving some of the cognitive aspects associated with SAD. However, phenelzine is usually less well tolerated than alternative treatments due to its associated dietary restrictions and adverse side-effect profile, including sedation and postural hypotension. Results with the reversible inhibitor of monoamine oxidase type A (RiMA) mociobemide are inconsistent. 

The synthesis of allylamines and corresponding a-amino-acids as inhibitors of clinically relevant enzymes has been reported. Seventeen 2-aryl-3-haloallylamine derivatives were prepared and evaluated as potential monoamine oxidase inhibitors, and found to be enzyme-activated irreversible inhibitors whose selectivity for... 

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. 

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. 

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

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. 

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. 

Selegiline is a relatively selective and irreversible inhibitor of monoamine oxidase type B, which has been used in the treatment of Parkinson s disease. It was originally suggested that selegiline may be neuroprotective. However, in a prospective double-blind study no such action was seen (1). On the other hand, selegiline does delay the start of disability, determined by the need for levodopa and progression of parkinsonian signs and symptoms (2). 

The monoamine oxidase (MAO) inhibitor deprenyl (Figure 7.9) is a propargylamine whose terminal acetylene reacts irreversibly with the MAO flavin moiety . Deprenyl also inactivates CYP2B1 relatively selectively with =... 

Monoamine oxidases (both MAO-A and MAO-B) also exist in peripheral tissue, specifically the gastrointestinal tract (GIT). In the GIT, they inhibit the first-pass metabolism of exogenous tyramine. Because of this property, treatment with non-selective irreversible MAOIs can result in the accumulation of tyramine and have the potential to precipitate a dangerous hypertensive crisis, the so-called cheese effect. This effect may occur more frequently in elderly than in younger patients, because the cardiovascular systems of the elderly are already compromised by age. Selective MAO-B inhibitors and reversible MAO-A inhibitors are free from this potentially fatal interaction. 

Deprenyl is a selective, irreversible inhibitor of the B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme increases with age. Deprenyl inhibits MAOB, which interferes with the reuptake of the monoamines dopamine, 5-HT, and epinephrine. Deprenyl decreases the aging effects on the enzyme... 

Monoamine oxidases are integral outer mitochondrial membrane proteins that catalyze the oxidative deamination of primary and secondary amines as well as some tertiary amines. MAO occurs as two enzymes, MAO-A and MAO-B, which differ in substrate selectivity and inhibitor sensitivity (Abell and Kwan, 2001 Edmondson et al., 2004 Shih et al., 1999). A number of MAO inhibitors have been developed for clinical use as antidepressants and as neuroprotective drugs. Clinically used drug substances include, among others, moclobemide, a relatively selective reversible MAO-A inhibitor, and L-deprenyl, an irreversible selective inhibitor of MAO-B. In vitro, clorgyline and L-deprenyl are used as selective irreversible inhibitors of MAO-A and B, respectively. (Note For in vitro studies using irreversible inhibitors, preincubation of the irreversible inhibitor with the enzyme prior to initiation of the substrate reaction is required for optimal inhibition.) Expressed MAO-A and MAO-B are not readily available via commercial resources however, MAO-A and MAO-B have been evaluated and are active in subcellular fractions. While monoamine oxidases are located in the mitochondria, many microsomal preparations are contaminated with monoamine oxidases during the preparation of the microsomal subcellular fraction and thus microsomes are sometimes used to evaluate monoamine oxidase activity in combination with selective inhibitors. 

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