{{Short description|Chemical compound}} {{Drugbox | verifiedrevid = 470606662 | IUPAC_name = 2-(Ethylthio)-10-[3-(4-methylpiperazin-1-yl)propyl]-10''H''-phenothiazine | image = Thiethylperazine.svg | image_class = skin-invert-image <!--Clinical data--> | tradename = Torecan, Norzine | Drugs.com = {{drugs.com|CONS|thiethylperazine}} | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category = | legal_AU = <!-- Unscheduled / S2 / S4 / S8 --> | legal_UK = <!-- GSL / P / POM / CD --> | legal_US = <!-- OTC / Rx-only --> | legal_status = | routes_of_administration = <!--Pharmacokinetic data--> | bioavailability = | protein_bound = 60% | metabolism = | elimination_half-life = | excretion = <!--Identifiers--> | IUPHAR_ligand = 7306 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 1420-55-9 | ATC_prefix = R06 | ATC_suffix = AD03 | ATC_supplemental = | PubChem = 5440 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00372 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5245 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 8ETK1WAF6R | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D02354 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 9544 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1378 <!--Chemical data--> | C = 22 | H = 29 | N = 3 | S = 2 | smiles = S(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(C)CC4)CC | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = XCTYLCDETUVOIP-UHFFFAOYSA-N }}
'''Thiethylperazine''' ('''Torecan''', '''Norzine''') is an antiemetic<ref>{{cite journal | vauthors = Tamboline BL, Mcgillivray DC, Bogoch A | title = The Effects of Thiethylperazine Dimaleate (Torecan) on Nausea and Vomiting | journal = Canadian Medical Association Journal | volume = 92 | issue = 8 | pages = 422–423 | date = February 1965 | pmid = 14261157 | pmc = 1928133 }}</ref> of the phenothiazine class. It is an antagonist of dopamine receptors (DRD1, DRD2, DRD4) as well as of 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub> receptors, mAChRs (1 through 5), α<sub>1</sub> adrenergic receptor and H<sub>1</sub> receptor.
Thiethylperazine activates the transport protein ABCC1 that clears beta-amyloid from brains of mice.<ref name="pmid21881209">{{cite journal | vauthors = 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 | display-authors = 6 | title = Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice | journal = The Journal of Clinical Investigation | volume = 121 | issue = 10 | pages = 3924–3931 | date = October 2011 | pmid = 21881209 | pmc = 3195473 | doi = 10.1172/JCI57867 }} * {{cite press release |date=September 1, 2011 |title=Alzheimer disease: Transport protein ABCC1 plays key role in clearing beta-amyloid from brains of mice |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2011/09/110901134628.htm}}</ref>
== Pharmacokinetics == === Distribution === Thiethylperazine is highly lipofilic and it binds with membranes and serum proteins (over 85%).<ref>{{cite web |title=Charakterystyka Produktu Leczniczego |url=https://rejestrymedyczne.ezdrowie.gov.pl/api/rpl/medicinal-products/6729/characteristic |website=rejestrymedyczne.ezdrowie.gov.pl |access-date=14 May 2023 |archive-url=https://web.archive.org/web/20221020064552/https://rejestrymedyczne.ezdrowie.gov.pl/api/rpl/medicinal-products/6729/characteristic |archive-date=October 20, 2022 |language=pl |url-status=live}}</ref> 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<ref>{{cite journal | vauthors = Rotrosen J, Angrist BM, Gershon S, Aronson M, Gruen P, Sachar EJ, Denning RK, Matthysse S, Stanley M, Wilk S | display-authors = 6 | title = Thiethylperazine; clinical antipsychotic efficacy and correlation with potency in predictive systems | journal = Archives of General Psychiatry | volume = 35 | issue = 9 | pages = 1112–1118 | date = September 1978 | pmid = 99115 | doi = 10.1001/archpsyc.1978.01770330086008 }}</ref> due to the antagonism of 5-HT<sub>2</sub> and D<sub>2</sub> receptors. It can cause extrapyramidal symptoms.{{Citation needed|date=June 2023|reason=Slovak SPC for Torecan explicitly mentions the risk of extrapyramidal side effects.}} 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.<ref>{{cite journal | vauthors = Khanderia U | title = Recurrent dystonic reactions induced by thiethylperazine | journal = Drug Intelligence & Clinical Pharmacy | volume = 19 | issue = 7–8 | pages = 550–551 | date = July 1985 | pmid = 4028959 | doi = 10.1177/106002808501900708 | s2cid = 44453678 }}</ref>
== 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'''.<ref>{{cite journal | vauthors = Bourquin JP, Schwarb G, Gamboni G, Fischer R, Ruesch L, Guldimann S, Theus V, Schenker E, Renz J | display-authors = 6 | title = Synthesen auf dem Phenothiazin-Gebiet. 1. Mitteilung. Mercaptophenothiazin-Derivate. | journal = Helvetica Chimica Acta | date = 1958 | volume = 41 | issue = 4 | pages = 1061–1072 | doi = 10.1002/hlca.19580410419 }}</ref><ref>{{cite journal | vauthors = Bourquin JP, Schwarb G, Gamboni G, Fischer R, Ruesch L, Guldimann S, Theus V, Schenker E, Renz J | display-authors = 6 | title = Synthesen auf dem Phenothiazin-Gebiet. 2. Mitteilung. N-substituierte Mercaptophenothiazin-Derivate. | journal = Helvetica Chimica Acta | date = 1958 | volume = 41 | issue = 4 | pages = 1072–1108 | doi = 10.1002/hlca.19580410420 }}</ref><ref>{{cite patent | country = US | number = 3336197 | gdate = 1967 | assign1 = Sandoz KK | inventor = Jany R, Bourquin jP, Gamboni G, Schwarb G | postscript = . }}</ref> 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''').
thumb|500px|center|class=skin-invert-image|Synthesis of thiethylperazine
== References == {{reflist}}
{{Antiemetics}} {{Antihistamines}} {{Dopamine receptor modulators}} {{Tricyclics}}
Category:Antiemetics Category:4-Methylpiperazin-1-yl compounds Category:Phenothiazines Category:Ethylthio compounds