Iproniazid

Clinical data
Trade names	Marsilid, others
AHFS/Drugs.com	International Drug Names
ATC code	N06AF05 (WHO)
Pharmacokinetic data
Bioavailability	1
Identifiers
IUPAC name N-isopropylisonicotinohydrazide
CAS Number	54-92-2 Y
PubChemCID	3748
DrugBank	DB04818 Y
ChemSpider	3617 Y
UNII	D892HFI3XA
KEGG	D02579 Y
ChEMBL	ChEMBL92401 Y
CompTox Dashboard(EPA)	DTXSID5023168
ECHA InfoCard	100.000.199
Chemical and physical data
Formula	C9H13N3O
Molar mass	179.223 g·mol−1
3D model (JSmol)	Interactive image
Density	1.084 g/cm3
Boiling point	265.9 °C (510.6 °F)
SMILES O=C(NNC(C)C)c1ccncc1
InChI InChI=1S/C9H13N3O/c1-7(2)11-12-9(13)8-3-5-10-6-4-8/h3-7,11H,1-2H3,(H,12,13) Y Key:NYMGNSNKLVNMIA-UHFFFAOYSA-N Y
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Iproniazid (Marsilid,Rivivol,Euphozid,Iprazid,Ipronid,Ipronin) is a non-selective,irreversiblemonoamine oxidase inhibitor (MAOI) of thehydrazine class.^[1][2] It is axenobiotic that was originally designed to treattuberculosis, but was later most prominently used as anantidepressant drug. However, it was withdrawn from the market because of itshepatotoxicity.^[3][4] The medical use of iproniazid was discontinued in most of the world in the 1960s, but remained in use inFrance until 2015.^{[citation needed]}

Iproniazid was originally developed for the treatment oftuberculosis,^[1] but in 1952, the compounds's antidepressant properties were discovered when researchers noted that patients became inappropriately happy when givenisoniazid, arelated antibiotic.^[1][5] Subsequently, adding a isopropyl chain onto isoniazid led to development as an antidepressant and was approved for use in 1958.^[1] It was withdrawn in most of the world a few years later in 1961 due to a high incidence ofhepatitis, and was replaced by lesshepatotoxic drugs such asphenelzine andisocarboxazid.^[1] Canada surprisingly withdrew iproniazid in July 1964 due to interactions with food products containing tyramine.^[6][7] 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 firstantidepressants ever marketed,dextroamphetamine (marketed asBenzedrine from 1935, for "mild depression", amid other indications)^[8] predates it; and herbs likecannabis andfrankincense have been used traditionally for millennia for, among other things, altering mood, although it was not until 2012 that one of the components of frankincense smoke was found to have antidepressant effects in mice.^[9][10][11]

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.^[12]

There are multiple routes to synthesize iproniazid. The most common precursor ismethyl isonicotinate which formesisonicotinohydrazide when it reacts withhydrazine.^[13] 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 selectivelyhydrogenated in the presence of a platinum catalyst and with water, alcohol or acetic acid as solvent.^[14][15]

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.^[16][17]

Iproniazid inhibits the activity ofmonoamine oxidases (MAOs) both directly and by formation of an active metabolite, isopropylhydrazine. The formation of isopropylhydrazine from iproniazid has been observed without MAOs present.^[12] Both iproniazid and isopropylhydrazine react near theactive site of MAOs. The reaction is a progressivefirst-order reaction with a highactivation energy. In the presence of oxygen it is anirreversible reaction, asdehydrogenation of iproniazid at the active site of the enzyme takes place. This dehydrogenation resembles the first step of amineoxidation. After dehydrogenation iproniazid further reacts with the enzyme.^[18]

Inhibition of MAOs by iproniazid iscompetitive and sensitive to changes in pH and temperature, similar to oxidation of the monoamine substrate. Inhibition cannot be reversed by addition of the substrate.^[18] Iproniazid is able to displace non-hydrazine inhibitors, but not other hydrazine inhibitors from the active site of the enzyme.^[12]

To increase the inhibition of monoamine oxidase,cyanide can be used. The reaction however remains oxygen-dependent.^[18] MAO inhibition can be decreased by addition ofglutathione, suggesting non enzymatic conjugation of either iproniazid or isopropylhydrazine with glutathione.^[18]

Iproniazid ismetabolized in the body. Iproniazid is converted to isopropyl hydrazine and isonicotinic acid in an initialhydrolysis reaction. Isopropyl hydrazine can either be released in the blood or it can be metabolically activated by microsomalCYP450 enzymes.^[19] This oxidation of isopropyl hydrazine is atoxification reaction that eventually can lead to the formation of analkylating agent: the isopropyl radical.^[3] Hepaticnecrosis was found in rats with doses as low as 10 mg/kg.^[19]

The presence of the isopropyl radical was indicated by another observed product of the metabolism of iproniazid: the gas propane.^[3]

Alkylating agents have the capability to bind to chemical groups such asamino,phosphate hydroxyl,imidazole andsulfhydryl groups. The formed isopropyl radical is able to form S-isopropyl conjugatesin vitro. This diminishes covalent binding to other proteins, however it was only observedin vitro.In vivo, hepatotoxic doses of isopropyl hydrazine, the precursor of the isopropyl radical, did not deplete sulfhydryl-group containing compounds.^[3]

The isopropyl radical formed as a result of the metabolism of iproniazid, is able to covalently bind to proteins and othermacromolecules in the liver. These interactions are the reason for the hepatotoxicity of iproniazid. Covalent binding results in livernecrosis by presumably changing protein function leading toorganelle stress and acute toxicity.^[20][21] However, the exact mechanism of how the binding of iproniazid derivatives to liver proteins would induce liver necrosis remains unclear.^[3]

Cytochrome P450 enzymes are present at the highest concentrations in the liver, causing most alkylating agents to be produced in the liver. This explains why the liver is mostly damaged by covalent binding of alkylating agents such as the isopropyl radical.^[19] Rat models and other animal models have shown that cytochrome P450 enzymes convert isopropyl hydrazine to alkylating compounds that induce liver necrosis. An inducer of a class of hepatic microsomal cytochrome P450 enzymes,phenobarbital, highly increased the chance of necrosis. In contrast, the compoundscobalt chloride,piperonyl butoxide and alpha-naphthylisothiocyanate inhibit microsomal enzymes which resulted in a decreased chance of necrosis due to isopropyl hydrazine.^[19]

Iproniazid can also be metabolised by O-dealkylation from iproniazid toacetone andisoniazid. Isoniazid can undergo further metabolism via multiple metabolic pathways, of which one eventually results in alkylating agents as well. This toxifying metabolic pathway includes N-acetylation. Reactions involving acetylation are influenced bygenetic variance: theacetylator phenotype. The toxicological response to isoniazid (and thus iproniazid) can therefore be subjected to interindividual differences.

Acetone can also be produced in alternative pathway as a metabolite of isopropyl hydrazine. It is eventually converted to CO₂ and exhaled.^[3]

Isonicotinic acid, formed during the hydrolysis of iproniazid, is described as a moderately toxic compound andallergen withcumulative effects.^[22] Isonicotinic acid is further metabolized by glycine-conjugation or glucuronic acid-conjugation.^[19][23]

Iproniazid can also interact with tyrosine-containing food products which may have toxic effects.^[6][7]

Excretion can occur via different routes: via thelungs, theurine,bile and sometimes via theskin orbreast milk. Iproniazid has a molecular weight of 179.219 g/mol, which is far below 500 g/mol, and it ishydrophilic (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.^[24]

Iproniazid can also bemetabolized and excreted afterwards in the form of one of its metabolites which can be found in the figure above.Isoniazid is hydrophilic^[24] 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 forisonicotinic acid andisonicotinoyl 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 asantidepressant. When it was discovered that iproniazid ishepatotoxic, it was replaced by medicinalxenobiotics that are less harmful to theliver. Examples of antidepressant drugs that are nowadays used instead of iproniazid areisocarboxazid,phenelzine, andtranylcypromine.^[3]

Drugs more effective for treatment of tuberculosis areisoniazid,pyrazinamide,ethambutol andrifampicin.^[25]

Iproniazid was designed to treattuberculosis, but its most significant positive effect is that it has a mood-stimulating property. Therefore, it was used as anantidepressant drug.^[7]

The most significant adverse effects of using iproniazid is thehepatotoxicity caused by itsmetabolites. Moreover, usage of iproniazid results in several adverse effects such asdizziness (when lying down),drowsiness,headaches,ataxia,numbness of the feet and hands, andmuscular twitching. However, these adverse effects disappear after approximately 10 weeks.^[26][27]

Rat animal models have been used to investigate thehepatotoxic (bio)chemical mechanism of iproniazid. Ametabolite of iproniazid, isopropyl hydrazine, was found to be a potenthepatotoxin in rats.^[3][19] Hepaticnecrosis was found in rats with doses as low as 10 mg/kg.^[19] It was predicted with admetSAR^[28] that iproniazid had a LD50 of 2.6600 mol/kg in rats.^[7]

See the table for experimentally determined LD50, TDLo and LDLo values of various organisms.^[29]

• Hydrazine (antidepressant)
• Isoniazid

• Monoamine oxidase inhibitors
• Hepatotoxins
• Hydrazides
• 4-Pyridyl compounds
• Withdrawn drugs
• Isopropylamino compounds

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