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-HT_2A, 5-HT_2C receptors, mAChRs (1 through 5), α₁ adrenergic receptor and H₁ receptor.

Thiethylperazine

Clinical data
Trade names	Torecan, Norzine
AHFS/Drugs.com	Micromedex Detailed Consumer Information
ATC code	R06AD03 (WHO)
Pharmacokinetic data
Protein binding	60%
Identifiers
IUPAC name 2-(Ethylthio)-10-[3-(4-methylpiperazin-1-yl)propyl]-10H-phenothiazine
CAS Number	1420-55-9 Y
PubChem CID	5440
IUPHAR/BPS	7306
DrugBank	DB00372 Y
ChemSpider	5245 Y
UNII	8ETK1WAF6R
KEGG	D02354 Y
ChEBI	CHEBI:9544 Y
ChEMBL	ChEMBL1378 Y
CompTox Dashboard (EPA)	DTXSID1023651
ECHA InfoCard	100.014.381
Chemical and physical data
Formula	C22H29N3S2
Molar mass	399.62 g·mol−1
3D model (JSmol)	Interactive image
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
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Thiethylperazine activates the transport protein ABCC1 that clears beta-amyloid from brains of mice.^[2]

Pharmacokinetics

Distribution

Thiethylperazine is highly lipofilic and it binds with membranes and serum proteins (over 85%).^[3] It accumulates in organs with high blood flow and penetrates the placenta. It cannot be removed with dialysis.

Metabolism

It is mainly metabolized in the liver and only 3% is eliminated unchanged. Thiethylperazine'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.^{[citation needed]} 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

One synthesis of thiethylperazine begins with a Goldberg reaction between 3-(ethylsulfanyl)aniline (1) and 2-chlorobenzoic acid (2) to give the diarylamine 3.^[6][7][8] The carboxyl in the anthranilic acid residue, having performed its activating function, is then thermolytically removed to form (4). Upon treatment with sulfur and iodine, we get predominantly the phenothiazine (5). The reaction may well be aided by the presence of the electron donating thioether at the para-position. Alkylation with 1-(γ-chloropropyl)-4-methylpiperazine (6) in the presence of sodamide affords thiethylperazine (7).

Synthesis of thiethylperazine