Tranylcypromine antidepressant

Csuk R, Schabel MJ et al (1996) Synthesis of the enantiomer of the antidepressant tranylcypromine. Tetrahedron Asymmetry 7 3505-3512... 

The antidepressant tranylcypromine 151 was made using the Evans box ligand 133. A different bulky ester 149 gave good ee but only moderate diastereoselectivity.35 The trans diastereoisomer hydrolyses faster than the cis so the free acid was essentially pure trans. Further reactions including a Curtius rearrangement with retention gave tranylcypromine 151. 

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). 

Like the Hofmann rearrangement, the Curtius rearrangement is often used commercially. For example, the antidepressant drug tranylcypromine is made by Curtius rearrangement of 2-phenylcyclopropanecarbonyl chloride. 

Despite public misconceptions, there is little firm evidence that the typical and atypical antidepressants produce dependence in clinical users. A review of 21 case reports of antidepressant addiction revealed that 12 were associated with tranylcypromine, although 8 of these 12 had a previous history of substance misuse (Haddad, 1999). Tranylcypromine s structural similarity to amphetamine may account for the significant number of reports of its addictive potential, but even here the term (mild) discontinuation reaction rather than withdrawal reaction should be used to allay any concerns patients might have (Haddad, 1999). 

Tranylcypromine sulfate is an antidepressant drug and an inhibitor of MAO. Its antidepressant effect is probably due to the accumulation of NE in the brain as a consequence of inhibition of the enzyme. The other MAO I currently used as an antidepressant is phenelzine sulfate. 

With most psychedelics, their activity can probably be considerably enhanced by prior (or possibly concomitant) use of a monoamine oxidase inhibitor (e.g., isocarboxazid (Marplan), nialamide (Niamid), phenelzine (Nardil), and tranylcypromine (Parnate)). Some compounds (e.g., DMT) which have no oral activity, can probably become orally active. These compounds are often prescribed as antidepressants, but it is not a good idea to use them frequently or in large doses. For antidotes to the hallucinogens see Amer. J. Hosp. Pharm. 30,80(1973). 

In the United States, there are presently three approved MAOis phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxizide (Marplan). These medications are all nonselective, irreversible inhibitors of the MAO enzymes. By nonselec-tive, it is meant that they block the actions of both the MAO-A and MAO-B enzyme subtypes. It is felt that blocking the MAO-B enzyme adds little to the effectiveness of these antidepressants but causes many of the problematic side effects. The MAOis are irreversible in that they deactivate the enzyme permanently. 

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). 

There are four classes of antidepressants tricyclic antidepressants (imipramine, trimipramine, amitriptyline, doxepin, desipramine, protriptyline, nortriptyline, amoxapine, maprotiline) monoaminooxidase (MAO) inhibitors (phenelzine, isocarboxazid, tranylcypromine) second-generation antidepressants or atypical antidepressants, which are a chemically dissimilar group of recently proposed drugs (bupropion, trazodone, fluoxetine) and amphetamines and other stimulators of the CNS (dextroamphetamine, methylphenidate). 

Due to the frequent unwanted effects and, in case of tranylcypromine, the numerous and dangerous interactions MAO-inhibitors are more and more replaced by the much less problematic SSRIs. Compounds belonging to this group are citalopram, escitalopram, fluoxetine, paroxetine and sertraline. They are used clinically in the therapy of depression, bulimia and obsessive-compulsive disorders. All SSRIs show a slow onset of action (1-2 weeks). They may induce insomnia and weight loss. The antidepressant ven-lafaxine inhibits both, serotonin and noradrenaline re-uptake and might therefore additionally induce hypertension. 

MAOI agents was synthesized and tested for antidepressant properties. Three MAOI agents are approved in the United States for use in major depression isocarboxazid (Marplan), phenelzine Nardil), and tranylcypromine (Parnate). 

Isocarboxazid, phenelzine, and tranylcypromine are irreversible nonselective inhibitors of both MAO-A and MAO-B. However, it appears that inhibition of MAO-A, not MAO-B, is important to the antidepressant action of these agents. 

E.M. Shepard, FI. Fleather, G.A. Juda, D.M. Dooley, Inhibition of six copper-containing amine oxidases by the antidepressant drug tranylcypromine, Biochim. Biophys. Acta 1647 (2003) 252-259. 

Since MAOIs have dangerous risks and since other, less obviously dangerous antidepressants exist, MAOIs are not often prescribed. However, when SSRIs fail, MAOIs may be used and are effective in many cases. Two of the older MAOI drugs still used to treat anxiety disorders are phenelzine, which is sold under the brand name Nardil, and tranylcypromine, which is sold under the brand name Parnate. 

Amsterdam JD Use of high dose tranylcypromine in resistant depression, in Refractory Depression. Edited by Amsterdam JD. NewYork, Raven, 1991,pp 123-130 Amsterdam JD, Berwish N Treatment of refractory depression with combination re-serpine and tricyclic antidepressant therapy. J Clin Psychopharmacol 7 238-242, 1987... 

Ravindran AV, Bialik RJ, Lapierre YD Primary early onset dysthymia, biochemical correlates of the therapeutic response to fluoxetine, 11 urinary metabolites of serotonin, norepinephrine and melatonin. J Affect Disord 31 119-123, 1994d Razani J, White KL, White J, et al The safety and efficacy of combined amitryptiline and tranylcypromine antidepressant treatment—a controlled trial. Arch Gen Psychiatry 40 657-661, 1983... 

The following side effects apply to the irreversible, nonselective MAOI antidepressants (phenelzine and tranylcypromine). The most common side effects are orthostatic hypotension, headache, insomnia, weight gain, sexual dysfunction, peripheral edema, and afternoon somnolence. Although MAOIs do not have significant affinity for muscarinic receptors, anticholinergic-like side effects are present at the beginning of treatment. Dry mouth is common but not as marked as in TCA therapy. Fortunately, the more serious side effects, such as hypertensive crisis and serotonin syndrome, are not common. 

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). 

Only minimal information is available about the pharmacokinetics of the traditional MAOIs (e.g., phenelzine, tranylcypromine) ( 308). Such data are probably less critical for these versus other antidepressants, because MAOIs are consumed by their mechanism of action (i.e., irreversible inhibition of MAO by covalently binding to the enzyme). This mechanism accounts for the fact that traditional MAOIs have half-lives of only 2 to 4 hours, but their effects persist for an extended period because of their irreversible inactivation of their target. These MAOIs undergo presystemic or first pass degradation, and, thus, genetic or acquired alterations in this metabolism could alter their bioavailability and hence their effects. 

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