Wikipedia

Iprindole

Iprindole, sold under the brand names Prondol, Galatur, and Tertran, is an atypical tricyclic antidepressant (TCA) that has been used in the United Kingdom and Ireland for the treatment of depression but appears to no longer be marketed.[4][5][6][7] It was developed by Wyeth and was marketed in 1967.[8] The drug has been described by some as the first "second-generation" antidepressant to be introduced.[9] However, it was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.[10]

Iprindole
Clinical data
Trade namesProndol, Galatur, Tertran
Other namesPramindole; WY-3263
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
MetabolismHepatic[3]
Elimination half-life52.5 hours[1]
ExcretionUrine, Feces[2]
Identifiers
  • 3-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indol-5-yl)-N,N-dimethylpropan-1-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.024.485 Edit this at Wikidata
Chemical and physical data
FormulaC19H28N2
Molar mass284.447 g·mol−1
3D model (JSmol)
  • c13c(n(c2ccccc12)CCCN(C)C)CCCCCC3
  • 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 checkY
  • Key:PLIGPBGDXASWPX-UHFFFAOYSA-N checkY
  (verify)

Medical uses

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Iprindole was used in the treatment of major depressive disorder in dosages similar to those of other TCAs.[5][11]

Contraindications

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Iprindole has been associated with jaundice and hepatotoxicity and should not be taken by alcoholics or people with pre-existing liver disease.[8][12][13][14] If such symptoms are encountered iprindole should be discontinued immediately.

Side effects

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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.[15] However, it still has significant antihistamine effects and therefore can produce sedation, though this is diminished relative to other TCAs similarly.[16] Iprindole also lacks significant alpha-blocking properties, and hence does not pose a risk of orthostatic hypotension.[16]

Overdose

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Main article: Tricyclic antidepressant overdose

In overdose, iprindole is much less toxic than most other TCAs and is considered relatively benign.[17] For instance, between 1974 and 1985, only two deaths associated with iprindole were recorded in the United Kingdom, whereas 278 were reported for imipramine, although imipramine is used far more often than iprindole.[10][17]

Interactions

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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.[3][18][19][20][21][22] It also inhibits its own metabolism.[21]

On account of these interactions, caution should be used when combining iprindole with other drugs.[3] As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentrations and prolongs their terminal half-lives by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity in the process.[23][24][25]

Pharmacology

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Pharmacodynamics

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See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Iprindole[26]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter 1,620–3,300 Human [27][28]
NETTooltip Norepinephrine transporter 1,262 Human [27]
DATTooltip Dopamine transporter 6,530 Human [27]
5-HT1A 2,800 Human [28]
5-HT2A 217–280 Human/rat [28][29]
5-HT2C 206 Rat [29]
α1 2,300 Human [30]
α2 8,600 Human [30]
β >10,000 Mammal [31][32]
D2 6,300 Rat [32]
H1 100–130 Human/rat [30][33]
H2 200–8,300 Guinea pig [32][34][35]
mAChTooltip Muscarinic acetylcholine receptor 2,100 Human [30][36]
σ1 >10,000 Rat [37]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Iprindole is unique compared to most other TCAs in that it is a very weak and negligible inhibitor of the reuptake of serotonin and norepinephrine and appears to act instead as a selective albeit weak antagonist of 5-HT2 receptors; hence its classification by some as "second-generation".[38][39][40] Additionally, iprindole has very weak/negligible antiadrenergic and anticholinergic activity and weak although possibly significant antihistamine activity; as such, side effects of iprindole are much less prominent relative to other TCAs, and it is well tolerated.[15] However, iprindole may not be as effective as other TCAs, particularly in terms of anxiolysis.[38][16] Based on animal research, the antidepressant effects of iprindole may be mediated through downstream dopaminergic mechanisms.[41]

The binding affinities of iprindole for various biological _targets are presented in the table to the right.[26] It is presumed to act as an inhibitor or antagonist/inverse agonist of all sites. Considering the range of its therapeutic concentrations (e.g., 63–271 nM at 90 mg/day),[1] only the actions of iprindole on the 5-HT2 and histamine receptors might be anticipated to be of possible clinical significance.[1] However, it is unknown whether these actions are in fact responsible for the antidepressant effects of iprindole. The plasma protein binding of iprindole and hence its free percentage and potentially bioactive concentrations do not seem to be known.

Pharmacokinetics

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Only one study appears to have evaluated the pharmacokinetics of iprindole.[1][42] A single oral dose of 60 mg iprindole to healthy volunteers has been found to achieve mean peak plasma concentrations of 67.1 ng/mL (236 nmol/L) after 2 to 4 hours.[1] The mean terminal half-life of iprindole was 52.5 hours, which is notably much longer than that of other TCAs like amitriptyline and imipramine.[1] Following chronic treatment with 90 mg/day iprindole for 3 weeks, plasma concentrations of the drug ranged between 18 and 77 ng/mL (63–271 nmol/L).[1] Theoretical steady-state concentrations should be reached by 99% within 15 to 20 days of treatment.[1]

Chemistry

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Iprindole is a tricyclic compound, specifically a cyclooctaindole (that is, an indole nucleus joined with a cyclooctyl ring), and possesses three rings fused together with a side chain attached in its chemical structure.[43] It is a tertiary amine TCA, although its ring system and pharmacological properties are very different from those of other TCAs.[15][44] Other tertiary amine TCAs that are similar to iprindole include butriptyline and trimipramine.[45][46] The chemical name of iprindole is 3-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indol-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H28N2 with a molecular weight of 284.439 g/mol.[47] The drug has been used commercially as both the free base and the hydrochloride salt.[47] The CAS Registry Number of the free base is 5560-72-5 and of the hydrochloride is 20432-64-8.[47]

History

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Iprindole was developed by Wyeth and was marketed in 1967.[8][48]

Society and culture

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Generic names

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Iprindole is the English and French generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française, while iprindole hydrochloride is its BANMTooltip British Approved Name.[47][4][49] Its generic name in Spanish and German is iprindol while its generic name in Latin is iprindolum.[4] Iprindole was originally known unofficially as pramindole.[47][4]

Brand names

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Iprindole has been marketed under the brand name Prondol by Wyeth in the United Kingdom and Ireland for the indication of major depressive disorder,[50] and has also been sold as Galatur and Tertran by Wyeth.[47]

Availability

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Iprindole was previously available in the United Kingdom and Ireland[50] but seems to no longer be available for medical use in any country.[4]

References

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  1. ^ a b c d e f g h Caillé G, de Montigny C, Besner JG (1982). "Quantitation of iprindole in plasma by GLC". Biopharmaceutics & Drug Disposition. 3 (1): 11–17. doi:10.1002/bdd.2510030103. PMID 7082775.
  2. ^ Sisenwine SF, Tio CO, Ruelius HW (April 1979). "The disposition of [14C]iprindole in man, dog, miniature swine, rhesus monkey and rat". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 9 (4): 237–246. doi:10.3109/00498257909038726. PMID 113942.
  3. ^ a b c Rotzinger S, Bourin M, Akimoto Y, Coutts RT, Baker GB (August 1999). "Metabolism of some "second"- and "fourth"-generation antidepressants: iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine". Cellular and Molecular Neurobiology. 19 (4): 427–442. doi:10.1023/A:1006953923305. PMID 10379419. S2CID 19585113.
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  6. ^ Dictionary of organic compounds. London: Chapman & Hall. 1996. ISBN 0-412-54090-8.
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