Phenelzine, structure

In the discussion of benzylamines, we have met medicinal agents that owe their activity to some particular functionality almost without reference to the structure of the rest of the molecule. The hydrazine group is one such function in that it frequently confers monamine oxidase-inhibiting activity to molecules containing that group. Such agents frequently find use as antidepressants. Thus, reduction of the hydrazone of phenyl-acetaldehyde (84) affords the antidepressant phenelzine (85). Similar treatment of the derivative of phenylacetone (86) gives pheniprazine (87). ... 

Carbonyl reagents, such as semicarbazide and phenelzine (27), are inactivators of SSAO. In a strategy that includes two inactivating structural motifs (allylamine and hydrazine), a series of allyl hydrazines including the series 28a-c as well as the fluoroallyl analogue 29 were prepared. Compounds 28a-c were potent irreversible inhibitors of SSAO, and compounds 28a,c had particularly good selectivity with respect to MAO inhibition. The presence of the vinyl fluoride in 29 had little effect on potency but did result in a loss in selectivity [82]. 

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. 

Figure 5.37 Structures of the enzyme inhibitors iproniazid, BNPP, isocarboxazid, and phenelzine. Abbreviation BNPP, bis-p-nitrophenyl phosphate.

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). 

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... 

Chemicae Structure Phenelzine is the prototype monoamine oxidase inhibitor... 

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... 

Nialamide [51-12-7] (30) and mebanazine [65-64-5] (31) are two MAO inhibitors marketed in Europe that have structural similarities to iproniazid and phenelzine, respectively. Both compounds are prepared by standard methods (35,36). 

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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