Thiethylperazine Explained

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 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.

Antipsychotic activity

Theithylperazine may possess antipsychotic activity[4] due to the antagonism of 5-HT2 and D2 receptors. It can cause extrapyramidal symptoms. Nevertheless, it was never marketed as an antipsychotic.

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

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).

Notes and References

  1. Tamboline BL, Mcgillivray DC, Bogoch A . The Effects of Thiethylperazine Dimaleate (Torecan) on Nausea and Vomiting . Canadian Medical Association Journal . 92 . 8 . 422–423 . February 1965 . 14261157 . 1928133 .
  2. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J . 6 . Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice . The Journal of Clinical Investigation . 121 . 10 . 3924–3931 . October 2011 . 21881209 . 3195473 . 10.1172/JCI57867 .
  3. Web site: Charakterystyka Produktu Leczniczego . rejestrymedyczne.ezdrowie.gov.pl . 14 May 2023 . https://web.archive.org/web/20221020064552/https://rejestrymedyczne.ezdrowie.gov.pl/api/rpl/medicinal-products/6729/characteristic . October 20, 2022 . pl . live.
  4. Rotrosen J, Angrist BM, Gershon S, Aronson M, Gruen P, Sachar EJ, Denning RK, Matthysse S, Stanley M, Wilk S . 6 . Thiethylperazine; clinical antipsychotic efficacy and correlation with potency in predictive systems . Archives of General Psychiatry . 35 . 9 . 1112–1118 . September 1978 . 99115 . 10.1001/archpsyc.1978.01770330086008 .
  5. Khanderia U . Recurrent dystonic reactions induced by thiethylperazine . Drug Intelligence & Clinical Pharmacy . 19 . 7–8 . 550–551 . July 1985 . 4028959 . 10.1177/106002808501900708 . 44453678 .