Iproniazid

Iproniazid was originally developed for the treatment of tuberculosis,[1] but in 1952, its antidepressant properties were discovered when researchers noted that patients became inappropriately happy when given isoniazid, a structural analog of iproniazid.[1][6] Subsequently N-isopropyl addition led to development as an antidepressant and was approved for use in 1958.[1] It was withdrawn in most of the world a few years later in 1961 due to a high incidence of hepatitis, and was replaced by less hepatotoxic drugs such as phenelzine and isocarboxazid.[1] Canada surprisingly withdrew iproniazid in July 1964 due to interactions with food products containing tyramine.[7][8] Nevertheless, iproniazid has historic value as it helped establish the relationship between psychiatric disorders and the metabolism of neurotransmitters.[4]

Although iproniazid was one of the first antidepressants ever marketed, amphetamine (marketed as Benzedrine from 1935, for "mild depression", amid other indications)[9] predates it; and frankincense has been marketed traditionally for millennia for, among other things, altering mood, although it was not until 2012 that one of the components of its smoke was found to have antidepressant effects in mice.[10] [11] [12]

The structure of iproniazid is chemically, in both structure and reactivity, similar to isoniazid. Iproniazid is a substituted hydrazine of which the isopropyl hydrazine moiety is essential for the inhibition of monoamine oxidase activity.[13]

This figure shows the multiple synthesis pathways towards iproniazid.

There are multiple routes to synthesize iproniazid. The most common precursor is methyl isonicotinate which formes isonicotinohydrazide when it reacts with hydrazine.[14] Isonicotinohydrazide can be converted into iproniazid via different pathways.

One synthesis pathway involves AcMe which results in the formation of N'-(propan-2-ylidene)isonicotinohydrazide. Subsequently, the C=N linkage is selectively hydrogenated in the presence of a platinum catalyst and with water, alcohol or acetic acid as solvent.[15][16]

In another pathway isonicotinohydrazide reacts with either 2-bromopropane or 2-chloropropane in an N-isopropyl addition reaction to the hydrazine moiety. This directly results in the formation of iproniazid.[17][18]

Iproniazid is a known monoamine oxidase inhibitor, it inhibits the activity of monoamine oxidases (MAOs) by itself and through an active metabolite, isopropylhydrazine. The formation of isopropylhydrazine from iproniazid has been observed without MAOs present.[13] Both iproniazid and isopropylhydrazine react near the active site of MAOs. The reaction is a progressive first-order reaction with a high activation energy. In the presence of oxygen it is an irreversible reaction, as dehydrogenation of iproniazid at the active site of the enzyme takes place. This dehydrogenation resembles the first step of amine oxidation. After dehydrogenation iproniazid further reacts with the enzyme.[19]

Inhibition of MAOs by iproniazid is competitive and sensitive to changes in pH and temperature, similar to oxidation of the monoamine substrate. Inhibition cannot be reversed by addition of the substrate.[19] Iproniazid is able to displace non-hydrazine inhibitors, but not other hydrazine inhibitors from the active site of the enzyme.[13]

To increase the inhibition of monoamine oxidase, cyanide can be used. The reaction however remains oxygen-dependent.[19] MAO inhibition can be decreased by addition of glutathione, suggesting non enzymatic conjugation of either iproniazid or isopropylhydrazine with glutathione.[19]

This figure shows the metabolism of iproniazid. The most important (proposed) metabolite is the isopropyl radical which is thought to be responsible for the heptatoxicity of iproniazid.[3][20]

Iproniazid is metabolized in the body. Iproniazid is converted to isopropyl hydrazine and isonicotinic acid in an initial hydrolysis reaction. Isopropyl hydrazine can either be released in the blood or it can be metabolically activated by microsomal CYP450 enzymes.[20] This oxidation of isopropyl hydrazine is a toxification reaction that eventually can lead to the formation of an alkylating agent: the isopropyl radical.[3] Hepatic necrosis was found in rats with doses as low as 10 mg/kg.[20]

Excretion can occur via different routes: via the lungs, the urine, bile and sometimes via the skin or breast milk. Iproniazid has a molecular weight of 179.219 g/mol, which is far below 500 g/mol, and it is hydrophilic (because of e.g. the N-H groups in the molecule). These two properties together indicate that iproniazid is likely to be excreted in the urine via the kidneys.[25]

Iproniazid can also be metabolized and excreted afterwards in the form of one of its metabolites which can be found in the figure above. Isoniazid is hydrophilic[25] and has a molecular weight of 137.139 g/mol. Isoniazid is therefore expected to be excreted via the urine, if it is not further metabolized in the body. The same holds for isonicotinic acid and isonicotinoyl glycine. Carbon dioxide and propane are gaseous which are presumably transported out of the body by exhalation via the lungs.

Iproniazid was originally produced as anti-tuberculosis medicine, but found to be more effective as antidepressant. When it was discovered that iproniazid is hepatotoxic, it was replaced by medicinal xenobiotics that are less harmful to the liver. Examples of antidepressant drugs that are nowadays used instead of iproniazid are isocarboxazid, phenelzine, and tranylcypromine.[3]

Drugs more effective for treatment of tuberculosis are isoniazid, pyrazinamide, ethambutol and rifampicin.[26]

Rat animal models have been used to investigate the hepatotoxic (bio)chemical mechanism of iproniazid. A metabolite of iproniazid, isopropyl hydrazine, was found to be a potent hepatotoxin in rats.[3][20] Hepatic necrosis was found in rats with doses as low as 10 mg/kg.[20] It was predicted with admetSAR[29] that iproniazid had a LD50 of 2.6600 mol/kg in rats.[8]

• Hydrazine (antidepressant)
• Isoniazid