Thiethylperazine

Thiethylperazine (Torecan, Norzine) is an antiemetic[1] of the phenothiazine class. It is an antagonist of dopamine receptors (DRD1, DRD2, DRD4) as well as of 5-HT2A, 5-HT2C receptors, mAChRs (1 through 5), α1 adrenergic receptor and H1 receptor.

Thiethylperazine
Clinical data
Trade namesTorecan, Norzine
AHFS/Drugs.comMicromedex Detailed Consumer Information
ATC code
Pharmacokinetic data
Protein binding60%
Identifiers
IUPAC name
  • 2-(ethylthio)-10-[3-(4-methylpiperazin-1-yl)propyl]-10H-phenothiazine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.014.381
Chemical and physical data
FormulaC22H29N3S2
Molar mass399.62 g·mol−1
3D model (JSmol)
SMILES
  • S(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(C)CC4)CC
InChI
  • InChI=1S/C22H29N3S2/c1-3-26-18-9-10-22-20(17-18)25(19-7-4-5-8-21(19)27-22)12-6-11-24-15-13-23(2)14-16-24/h4-5,7-10,17H,3,6,11-16H2,1-2H3 Y
  • Key:XCTYLCDETUVOIP-UHFFFAOYSA-N Y
  (verify)

Thiethylperazine activates the transport protein ABCC1 that clears beta-amyloid from brains of mice.[2]

Pharmacokinetics[3]

Distribution

This drug is highly lipofilic and it binds with membranes and serum proteins (over 85%). It accumulates in organs with high blood flow and penetrates the placenta. It cannot be removed with dialysis.

Metabolism

It is mainly metabolised in the liver and only 3% is eliminated unchanged. Torecan's half-life is 12 h.

Teratogenicity

In toxic doses above the terapeutic window, it increases the rate of cleft palate occurrence.

Antypsychotic activity

Theithylperazine may possess antypsychotic activity[4] due to the antagonism of 5-HT2 and D2 receptors. Because of this, it would not cause extrapyramidal symptoms. Nevertheless, it was never marketed as such drug.

One cause of acute dystonia occurred in a 19-year-old male patient after discontinuation of this drug.[5]

Overdose

Signs of acute thiethylperazine overdose include: extrapyramidal symptoms, confusion, convulsions, respiratory depression and hypotension.

Synthesis
Thieme Synthesis:[6][7] Patent:[8]

Goldberg reaction between 3-(ethylsulfanyl)aniline [1783-82-0] (1) and 2-chlorobenzoic acid [118-91-2] (2) to give the diarylamine, CID:82254530 (3). The carboxyl in the anthranilic acid residue, having performed its activating function, is then thermolytically removed to form [68083-49-8] (4). Upon treatment with sulfur and iodine, we get predominantly the phenothiazine [46815-10-5] (5); The rxn may well be aided by the presence of the electron donating thioether at the para-position. Alkylation with 1-(ɣ̞-chloropropyl)-4-methylpiperazine [104-16-5] (6) in the presence of sodamide affords Thiethylperazine (7).

References
  1. Tamboline, B. L.; McGillivray, D. C.; Bogoch, A. (1965-02-20). "The Effects of Thiethylperazine Dimaleate (Torecan) on Nausea and Vomiting". Canadian Medical Association Journal. 92 (8): 422–423. ISSN 0008-4409. PMC 1928133. PMID 14261157.
  2. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, et al. (October 2011). "Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice". The Journal of Clinical Investigation. 121 (10): 3924–31. doi:10.1172/JCI57867. PMC 3195473. PMID 21881209.
  3. https://rejestrymedyczne.ezdrowie.gov.pl/api/rpl/medicinal-products/6729/characteristic. {{cite web}}: Missing or empty |title= (help)
  4. Rotrosen, J.; Angrist, B. M.; Gershon, S.; Aronson, M.; Gruen, P.; Sachar, E. J.; Denning, R. K.; Matthysse, S.; Stanley, M.; Wilk, S. (September 1978). "Thiethylperazine; clinical antipsychotic efficacy and correlation with potency in predictive systems". Archives of General Psychiatry. 35 (9): 1112–1118. doi:10.1001/archpsyc.1978.01770330086008. ISSN 0003-990X. PMID 99115.
  5. Khanderia, Ujjaini (July 1985). "Recurrent Dystonic Reactions Induced by Thiethylperazine". Drug Intelligence & Clinical Pharmacy. 19 (7–8): 550–551. doi:10.1177/106002808501900708. ISSN 0012-6578.
  6. Bourquin, J.-P.; Schwarb, G.; Gamboni, G.; Fischer, R.; Ruesch, L.; Guldimann, S.; Theus, V.; Schenker, E.; Renz, J. (1958). "Synthesen auf dem Phenothiazin-Gebiet. 1. Mitteilung. Mercaptophenothiazin-Derivate". Helvetica Chimica Acta. 41 (4): 1061–1072. doi:10.1002/hlca.19580410419.
  7. Bourquin, J.-P.; Schwarb, G.; Gamboni, G.; Fischer, R.; Ruesch, L.; Guldimann, S.; Theus, V.; Schenker, E.; Renz, J. (1958). "Synthesen auf dem Phenothiazin-Gebiet. 2. Mitteilung. N-substituierte Mercaptophenothiazin-Derivate". Helvetica Chimica Acta. 41 (4): 1072–1108. doi:10.1002/hlca.19580410420.
  8. Renz Jany, et al. U.S. Patent 3,336,197 (1967 to Sandoz KK).


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