Thiethylperazine

Thiethylperazine (Torecan, Norzine) is an antiemetic 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.

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 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.

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).