Iproniazid, structure

Tricyclic Antidepressants (TCAs). Like iproniazid, the first TCA was also developed in the 1950s for another purpose. Imipramine (Tofranil) is structurally similar to the early antipsychotics and was hoped to provide an alternative to chlor-promazine (Thorazine). It proved to be a poor antipsychotic but was surprisingly found to be an effective antidepressant. The tricyclics are so named because a three-ringed structure forms the hub of the molecule. 

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-... 

Shortly after iproniazid was shown to have antidepressant properties, imipramine was introduced as the first tricyclic antidepressant. These drugs received the name tricyclic because their structure contains three molecular rings. At first, imipramine was investigated as a possible treatment for the psychotic episodes associated with schizophrenia, a severe mental disorder that causes hallucinations and delusions, because it was chemically similar to another effective anti-schizophrenia drug. Imipramine did not reduce the severity of psychotic episodes, but it did elevate the mood of the patients who took it. In the late 1950s, it was released in the United States under the name Tofranil for the treatment of depression. 

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

Iproniazid is an antidepressant drug with f-Pr in both structure and name. 0... 

The early pioneering work by Zeller et al. (115) on the potent MAO inhibitory effect of iproniazid—a structural modification of the tuberculostat Isoniazid—and his realization of the physiologic consequences that might arise from such a profound alteration in catecholamine metabolism, the actual confirmation by Brodie, Pletscher, and Shore (27) of the rise in brain monoamine levels following the administration of iproniazid and JB-516 (a-methylphen-ethylhydrazine), and the early euphoric effects noted by Selikoff, Robitzek, and Omstein (96) in tuberculosis patients on iproniazid therapy led Kline and his associates (67) to investigate the possible application of iproniazid in the treatment of mental depression. It was their conclusion that MAO inhibition and antidepressant effect had a causal relationship and that a new approach for the treatment of mental depression had been uncovered. The subject of the MAO inhibitors has been reviewed extensively up to 1960 by Pletscher, Gey, and Zeller (84) and by Biel, Horita, and Drukker (21) to 1963, in comprehensive reviews of the chemistry, biochemistry, pharmacology, clinical application, and structure-activity relationships of the MAO inhibitors. 

Levene studied the relationship between structure and activity amongst the nitriles and related compounds. Modification of the nitrile group causes loss of activity. Substitution of the amino group usually destroys activity but methyleneaminoacetonitrile is active. Cyanoacetyhydrazide retains about one third of the activity of the aminoacetonitrile. Activity is also present in semicarbazide, hydrazine and several hydrazides, including isoniazid. The inhibitory effect of aminoacetonitrile, iproniazid and semicarbazide on granulation tissue formation has been confirmed . 

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). 

Notice how the propyl part of isopropyl still indicates three carbon atoms they are just joined together in a different way—in other words, as an isomer of the straight chain propyl group. Sometimes, to avoid confusion, the straight chain alkyl groups are called -alkyl (for example, -Pr, -Bu)—n for normal —to distinguish them from their branched counterparts. Iproniazid is an antidepressant drug with i-Pr in both structure and name. Isopropyl may be abbreviated to i-Pr, Pr, or Pr. We shall use the first in this book, but you may see the others used elsewhere. 

Metabolism studies on hydrazines alkylated at one position have also been performed in vivo 84). Iproniazid, which is structurally related to isoniazid, was shown to be metabolized to reactive components which became covalently bound to hepatic tissue. The radiolabel was contained in the isopropyl moiety (555). The proposed metabolic fate of iproniazid is also illustrated in Fig. 17. The major difference between these activation pathways is that the reactive species formed metabolically from isoniazid is an acylating agent while in the case of iproniazid an alkylating agent is formed. 

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