Iprindole

Iprindole

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Systematic (IUPAC) name
3-(6,7,8,9,10,11-Hexahydro- 5H-cycloocta[b]indol-5-yl)-N,N-dimethylpropan-1-amine
Clinical data
Legal status	℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hepatic
Biological half-life	52.5 hours
Excretion	Urine, Feces
Identifiers
CAS Number	5560-72-5 Y
ATC code	N06AA13 (WHO)
PubChem	CID: 21722
ChemSpider	20417 Y
UNII	69U0IKR8FP Y
KEGG	D04605 Y
ChEMBL	CHEMBL126224 Y
Chemical data
Formula	C19H28N2
Molecular mass	284.439 g/mol
SMILES c13c(n(c2ccccc12)CCCN(C)C)CCCCCC3
InChI InChI=1S/C19H28N2/c1-20(2)14-9-15-21-18-12-6-4-3-5-10-16(18)17-11-7-8-13-19(17)21/h7-8,11,13H,3-6,9-10,12,14-15H2,1-2H3 Y Key:PLIGPBGDXASWPX-UHFFFAOYSA-N Y
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Iprindole (Prondol, Galatur, Tertran), formerly known as pramindole, is a tricyclic antidepressant (TCA) used in Europe for the treatment of depression. It was introduced by Wyeth and has been used clinically since 1967. Notably, iprindole was the first second-generation antidepressant to be launched.

Iprindole is unique compared to most other TCAs in that it is a relatively weak inhibitor of the reuptake of serotonin and norepinephrine and instead acts predominantly as an antagonist of 5-HT₂ receptors, hence its classification as 'second-generation'. Additionally, side effects of iprindole are much less prominent relative to other TCAs and it is well tolerated. However, iprindole's efficacy may not be as great as other TCAs, especially in regards to anxiety relief.

Availability

Iprindole has been sold under the trade name Prondol by Wyeth in the United Kingdom and Ireland for the indication of major depressive disorder, and has also been sold as Galatur and Tertran by Wyeth as well.

Chemistry

On a structural level, iprindole differs from other TCAs in that it contains an indole nucleus, similarly to the heterocyclic antipsychotic oxypertine, and has an eight-membered and saturated third ring.

Pharmacology

Iprindole acts as an antagonist (or inverse agonist) of the following receptors:

• 5-HT_1A receptor (K_d = 2,800 nM)
• 5-HT_2A receptor (K_i = 217 nM)
• 5-HT_2C receptor (K_i = 206 nM)
• α₁-adrenergic receptor (K_d = 2,300 nM)

• α₂-adrenergic receptor (K_d = 8,600 nM)
• H₁ receptor (K_d = 130 nM)
• H₂ receptor (K_d = 1,980 nM)
• mACh receptors (K_d = 2,100 nM)

And as an inhibitor of the following transporters:

• SERT (K_d = 1,620 nM)
• NET (K_d = 1,262 nM)
• DAT (K_d = 6,530 nM)

It has negligible affinity (>10,000 nM) for β-adrenergic and sigma receptors.

Dosage

Iprindole is used in doses of 30–180 mg daily.

Side effects

Anticholinergic side effects such as dry mouth and constipation are either greatly reduced in comparison to imipramine and most other TCAs or fully lacking with iprindole. However, it still has potent antihistamine effects and therefore can produce sedation, though this is diminished relative to imipramine as well, perhaps due to iprindole lacking significant alpha-blocking properties.

Contraindications

Iprindole has been associated with jaundice and hepatotoxicity and should not be taken by alcoholics or people with pre-existing liver disease. If such symptoms are encountered iprindole should be discontinued immediately.

Interactions

Iprindole has been shown to be a potent inhibitor of the aromatic hydroxylation and/or N-dealkylation-mediated metabolism of many substances including, but not limited to octopamine, amphetamine, methamphetamine, fenfluramine, phenelzine, tranylcypromine, trimipramine, and fluoxetine, likely via inactivating cytochrome P450 enzymes. It also inhibits its own degradation.

On account of these interactions, caution should be used when combining iprindole with other drugs. As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentrations and prolongs their half-lives by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity in the process.

Overdose

In overdose, iprindole is much less toxic than most other TCAs and is considered relatively benign. For instance, between 1974 and 1985, only two deaths associated with iprindole were recorded in the United Kingdom, whereas 278 were reported for imipramine. However, it should be noted that imipramine is prescribed much more often than iprindole, and for that reason this comparison is likely not entirely representative of iprindole's true capacity for fatality in overdose.

See also

• Trimipramine