Iproniazid

Antidepressant

Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It is a xenobiotic that was originally designed to treat tuberculosis, but was later most prominently used as an antidepressant drug. However, it was withdrawn from the market because of its hepatotoxicity. The medical use of iproniazid was discontinued in most of the world in the 1960s, but remained in use in France until its discontinuation in 2015.

Iproniazid was originally developed for the treatment of tuberculosis, Subsequently N isopropyl addition led to development as an antidepressant and was approved for use in 1958. Nevertheless, iproniazid has historic value as it helped establish the relationship between psychiatric disorders and the metabolism of neurotransmitters. 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.

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.

There are multiple routes to synthesize iproniazid. The most common precursor is methyl isonicotinate which formes isonicotinohydrazide when it reacts with hydrazine. 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. 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.

Iproniazid inhibits the activity of monoamine oxidases (MAOs) both directly and by formation of an active metabolite, isopropylhydrazine. The formation of isopropylhydrazine from iproniazid has been observed without MAOs present. 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.]] 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. However, the exact mechanism of how the binding of iproniazid derivatives to liver proteins would induce liver necrosis remains unclear. Isonicotinic acid is further metabolized by glycine conjugation or glucuronic acid conjugation.

Iproniazid can also interact with tyrosine containing food products which may have toxic effects. 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

Iproniazid was designed to treat tuberculosis, but its most significant positive effect is that it has a mood stimulating property. Therefore, it was used as an antidepressant drug.

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. that iproniazid had a LD50 of 2.6600 mol/kg in rats. +OrganismTest TypeRouteReported Dose (mg/kg)ReferenceDogLD50oral95 Annals of the New York Academy of Sciences. Vol. 80, Pg. 626, 1959. HumanTDLooral2.143 /DActa Neurologia et Psychiatrica Belgica. Vol. 59, Pg. 977, 1959. Human LDLooral14 /2W ICanadian Medical Association Journal. Vol. 78, Pg. 131, 1958. MonkeyLD50oral640Annals of the New York Academy of Sciences. Vol. 80, Pg. 626, 1959. MouseLD50Intramuscular615American Review of Tuberculosis. Vol. 65, Pg. 376, 1952. MouseLD50intraperitoneal475Japanese Journal of Pharmacology. Vol. 13, Pg. 186, 1963. MouseLD50intravenous719American Review of Tuberculosis. Vol. 65, Pg. 376, 1952. MouseLD50oral440Pharmaceutical Chemistry Journal Vol. 30, Pg. 750, 1996. MouseLD50subcateneous730American Review of Tuberculosis. Vol. 65, Pg. 376, 1952. RabbitLD50intravenous117American Review of Tuberculosis. Vol. 65, Pg. 376, 1952. RabbitLD50oral125American Review of Tuberculosis. Vol. 65, Pg. 376, 1952. RabbitLDLoskin2000Huntingdon Research Center Reports. Vol. , Pg. , 1972. RatLD50subcutaneous538Japanese Journal of Pharmacology. Vol. 13, Pg. 186, 1963. RatLD50unreported350Nature. Vol. 185, Pg. 532, 1960. RatLD50oral365Journal of Pharmacology and Experimental Therapeutics. Vol. 119, Pg. 444, 1957. Rat LD50intraperitoneal375Arzneimittel Forschung. Drug Research. Vol. 20, Pg. 363, 1970.