Tranylcypromine structure

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). 

Figure 5 Structures of phenylzine 15, tranylcypromine 16, and the peptide substrate mimics 17-19.

Mimasu, S., Sengoku, T, Fukuzawa, S., Umehara, T. and Yokoyama, S. (2008) Crystal structure of histone demethylase LSDl and tranylcypromine at 2.25 A. Biochemical and Biophysical Research Communications, 366 (1), 15-22. 

Tranylcypromine ( rans-2-phenylcyclopropylamine, TCP, 8a) has close structural similarity to amphetamine (2-amino-1-phenylpropane) and is known as a nonhydrazine, nonselective, and irreversible inhibitor of both MAO A and B. It is also a potent reversible inhibitor of CAOs [36,37], Tranylcypromine has an important clinical use for treatment of certain depressive illnesses, particularly of nonendo-genous and atypical depressions and depressions associated with anxiety, agitation, phobias, and anergia [38-40], In combination with lithium, it is also applied for treatment of refractory depression [41], Recent reports also discussed MAO inhibitors as useful agents against neurodegenerative disorders such as Parkinson s or Alzheimer s diseases [42], Despite impressive clinical successes, clinical use of tranylcypromine and other MAO inhibitors is limited by various problems, including the cheese effect discussed in Section 1,... 

Structurally, all MAOIs are either hydralazines or nonhydralazines. Iproniazid, the first MAOI used for depression, is a hydralazine. There are currently two hydralazines available, phenelzine and isocarboxazid. Tranylcypromine is a nonhydralazine with a unique structure. Although tranylcypromine is considered to be a reversible inhibitor of MAO, clinically, the return of normal enzymatic activity is delayed, similar to phe-... 

Current MAOIs include the hydrazine derivatives phenelzine and isocarboxazid and the non-hydrazines tranylcypromine, selegiline, and moclobemide (the latter is not available in the USA). The hydrazines and tranylcypromine bind irreversibly and nonselectively with MAO-A and -B, whereas other MAOIs may have more selective or reversible properties. Some of the MAOIs such as tranylcypromine resemble amphetamine in chemical structure, whereas other MAOIs such as selegiline have amphetamine-like metabolites. As a result, these MAOIs tend to have substantial CNS-stimulating effects. 

This compound, DMCPA, was modeled directly after the structure of DOM, with the 2,5-dimethoxy-4-methyl substitution pattern. Another analogue of tranylcypromine, similarly modeled, is 3,4,5-trimethoxytranylcypromine, ortrans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine (TMT). It has been evaluated at levels of only 13 milligrams orally, and at this dose there were no hints of central activity. 

Tranylcypromine is a non-hydrazine monoamine oxidase (MAO) inhibitor with actions and uses similar to those of phenelzine, but with less prolonged inhibition. Its half-life is 90-190 minutes. It is structurally related to amfetamine, to which it is metabolized in overdose (1). 

Four cases of addiction to tranylcypromine have been described, in addition to the three reported since 1965 (2). The dosage was 150-300 mg/day. The mild euphoriant properties of tranylcypromine reflect its structural resemblance to amfetamine, and probably account for tolerance and addiction in predisposed individuals. Tranylcypromine abuse in 18 patients has been reviewed (3), and two further reports have appeared (SEDA-17,17) (4). In one case (5), the patient took 440 mg/day without any adverse effects. The patient reported that she was longing for the energizing effect of the drug and for the feeling of freedom and power. Withdrawal resulted in repeated generalized seizures and status epilepticus. 

The dosage was 150-300 mg/day. The mild euphoriant properties of tranylcypromine reflect its structural resemblance to amfetamine, and probably account for tolerance and addiction in predisposed individuals. Tranylcypromine abuse in 18 patients has been reviewed... 

The clinically u.scful MAOl antidepre.ssanls are nonselec-tive between inhibiting metabolism of NE and S-HT. AgenLs selective for a MAO that degrades. S-HT have been under study for some lime. The structures of phenelzine and tranylcypromine are given in Table IS-4... 

The basic concept regarding MAO inhibitors is straightforward. These compounds prevent MAO-catalyzed deamination of biogenic amines (5-HT, NE, DA) following their reuptake into the nerve terminal from synaptic cleft. As a result, higher concentrations of the neurotransmitters will be stored in the vesicles and become available for release from the presynaptic terminals on demand. Of the two MAO isozymes, type A deaminates NE and 5-HT preferentially MAO-B seems to exhibit a preference for phenethylamine. Many of the previously marketed MAO inhibitors have been withdrawn because serious hepatotoxicities were demonstrated. Only three have survived. The hydrazine phenelzine, the hydrazide isocarboxazide, and the amphetaminelike structured tranylcypromine (Table 12-17). The problem with these drugs is certainly not lack of effectiveness, but... 

The MAO inhibitor tranylcypromine is amphetamine-like in structure but interacts only weakly at DA transporters. The phenylpiperazine nefazodone, and to a lesser extent, the structurally related trazodone have weak inhibitory actions on 5-HT transport nefazodone also may have a minor effect on NE transport. This agent also has a prominent direct antagonistic effect at S-HT receptors that may contribute to antidepressant and anxiolytic activity. Both drugs also may inhibit presynaptic 5-HTj subtype autoreceptors to enhance neuronal release of 5-HT, though they probably also exert at least partial-agonist effects on postsynaptic 5-HTj receptors. Trazodone also blocks cerebral and Hj receptors, possibly contributing to its tendency to induce priapism and sedation, respectively. 

Tranylcypromine is a chiral monoamine oxidase inhibitor used in the treatment of depression. The drug is similar to mefloquine in that it is contains a diastereomeric structure but is only administered as the 50 50 combination of the (- -)-lS,2R and (—)-lR,2S species. The enantiomers possess differences in their pharmacological properties in that (-I-) tranylcypromine is much more effective than its antipode in MAO inhibition, but the (—) enantiomer causes greater diminution of catecholamine reuptake and release than (-I-) enantiomer [147]. With respect to its pharmacokinetics (Table 1), the (-I-) enantiomer seemed to be cleared via the oral route 4 to 8 times more rapidly than antipode based on significantly... 

There appear to be no reports of adverse reactions during the concurrent use of MAOIs and carbamazepine. However, the manufacturers of carbamazepine say that concurrent use should be avoided because of the close structural similarity between carbamazepine and the tricyclic antidepressants (and therefore the theoretical risk of an adverse interaction). They suggest that MAOIs should be discontinued at least 2 weeks before carbamazepine is started. Several reports describe successful use of carbamazepine and MAOIs, namely tranylcypromine, phenelzine, and moclobemide. Bearing in mind that the MAOIs and the tricyclics can be given together under certain well controlled conditions (see MAOIs or RIMAs + Tricyclic and related antidepressants , p.ll49), the warning about the risks may possibly prove to be overcautious. Note that, rarely, the MAOIs have been seen to cause convulsions. 

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