Tiotixene

Tiotixene
Clinical data
Trade namesNavane
Other namesThiothixene (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa682867
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability~100%
MetabolismHepatic
Elimination half-life10–20 hours
ExcretionGastrointernal tract, faeces
Identifiers
  • (9Z)-N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene]-9H-thioxanthene-2-sulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.233.356 Edit this at Wikidata
Chemical and physical data
FormulaC23H29N3O2S2
Molar mass443.62 g·mol−1
3D model (JSmol)
  • O=S(=O)(N(C)C)c2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN4CCN(C)CC4
  • InChI=1S/C23H29N3O2S2/c1-24(2)30(27,28)18-10-11-23-21(17-18)19(20-7-4-5-9-22(20)29-23)8-6-12-26-15-13-25(3)14-16-26/h4-5,7-11,17H,6,12-16H2,1-3H3/b19-8- checkY
  • Key:GFBKORZTTCHDGY-UWVJOHFNSA-N checkY
  (verify)

Tiotixene, or thiothixene is a typical antipsychotic agent currently sold under the brand name Navane which is predominantly utilised to treat acute and chronic schizophrenia.[2] Beyond its primary indication, it can exhibit a variety of effects common to neuroleptic drugs including anxiolytic, anti-depressive, and anti-aggressive properties.[3]

The drug was first synthesized and marketed in 1967 under the pharmaceutical company Pfizer.[2][4][5][6] While the usage of the drug has declined in recent decades, the drug continues to be manufactured and prescribed in the US and Canada.[6]

Being a member of the thioxanthene class, it is chemically related to other typical neuroleptic agents such as chlorprothixene, clopenthixol, flupenthixol, and zuclopenthixol. Tiotixene also shares structural similarities with thioproperazine and pipotiazine, which are members of the phenothiazine class.

Medical uses

Tiotixene is a widely used drug for the treatment of various psychiatric disorders such as schizophrenia, bipolar disorder, mania, and behavioural disturbances.[7] The drug regulates behaviour and thoughts, and can also exhibit an anti-depressive effect.[3][8]  

The side effect profile is similar to related antipsychotic agents, displaying weight gain, mental distress, and inability to sit still. Other possible symptoms include anticholinergic side effects such as insomnia, blurred vision, and dry mouth.[9][10] Less frequently encountered side effects are drug-induced movement disorders such as Parkinson's syndrome and tardive dyskinesia.[11][12]

The results of various dose-response studies (10–60 mg) indicate a stimulating effect at lower doses, which diminishes as higher doses are administered.[13] Overall, the efficacy of thiothixene when compared to other antipsychotic drugs was evaluated to be at least as effective regardless of the optimum dosage.[13][14][15]

Pharmacology

Pharmacokinetics

As common with tricyclic psychotherapeutic agents, tiotixene is rapidly and extensively absorbed.[16] Peak serum concentration of the drug is achieved after 1–3 hours.[17] After absorption, the compound and its metabolites are spread widely throughout the body.  

The drug's metabolism proceeds rapidly and primarily in the liver.[2][16] Although N-demethyltiotixene was identified as its major metabolite, the metabolic mechanisms remain elusive.[2][18] After metabolism, most of the material is excreted through the faeces.[16]

Pharmacodynamics

Tiotixene[19]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter 3,162–3,878 Human [19][20]
NETTooltip Norepinephrine transporter 30,200 Human [19][20]
DATTooltip Dopamine transporter 3,630 Human [19][20]
5-HT1A 410–912 Human [19][21][20]
5-HT1B 151 Human [19]
5-HT1D 659 Human [19]
5-HT1E >10,000 Human [19]
5-HT2A 50–89 Human [21][20]
5-HT2C 1,350–1,400 Human [21][20]
5-HT3 1,860 Human [19][20]
5-HT5A 361 Human [19]
5-HT6 208–320 Human [19][21][20]
5-HT7 15.5 Human [19][21][20]
α1 19 ND [20]
  α1A 11–12 Human [19][21]
  α1B 35 Human [19]
α2 95 ND [20]
  α2A 80 Human [19][21]
  α2B 50 Human [19][21]
  α2C 52 Human [19][21]
β1 >10,000 Human [19]
β2 >10,000 Human [19]
D1 51–339 Human [19][20]
D2 0.03–1.4 Human [19][21][22]
D3 0.3–186 Human [22][20]
D4 203–363 Human [19][20]
D4.2 410–685 Human [22]
D5 261 Human [19]
H1 4.0–12 Human [19][21][23]
H2 411 Human [19]
H3 1,336 Guinea pig [19]
H4 >10,000 Human [19]
mAChTooltip Muscarinic acetylcholine receptor 3,310 ND [20]
  M1 ≥2,820 Human [19][20]
  M2 ≥2,450 Human [19][20]
  M3 ≥5,750 Human [19][21][20]
  M4 >10,000 Human [19]
  M5 5,376 Human [19]
σ 1,780 ND [20]
Values are Ki (nM). The smaller the value,
the more strongly the drug binds to the site.
See also: Antipsychotic § Mechanism of action, and Antipsychotic § Comparison of medications

Tiotixene shares its mechanism with related thioxanthenes which are all fundamentally used to control schizophrenia. Their mechanism of action involves the inhibition of different receptors, including 5-HT (serotonin), dopaminergic, histaminergic, and adrenergic receptors.[24] Blocking these receptors results in a reduction of synaptic levels of dopamine, serotonin, and other neurotransmitters that are involved with abnormal excitement in the brain during psychoses.[24][25] This reduction of abnormal neurotransmission activity tends to alleviate the psychotic indications associated with schizophrenia.[26]

Tiotixene acts primarily as a highly potent antagonist of the dopamine D2 and D3 receptors (subnanomolar affinity).[19] It is also an antagonist of the histamine H1, α1-adrenergic, and serotonin 5-HT7 receptors (low nanomolar affinity), as well as of various other receptors to a much lesser extent (lower affinity).[19] It does not have any anticholinergic activity.[19] Antagonism of the D2 receptor is thought to be responsible for the antipsychotic effects of tiotixene.

Toxicology

Thiothixene has demonstrated toxicity in animal studies and isolated human tissue, displaying cytotoxic effects against various cell types. Observed toxic effects included growth inhibition of mouse fibroblasts, inhibition of protein synthesis by human glioma cells, and inhibition of leukocyte DNA synthesis.[27][28]

Other compounds within the thioxanthene class have demonstrated hepatotoxicity in rodent experiments, and although anecdotal reports of thiothixene-induced liver failure exist, scientific data regarding the correlation lacks.[29] The absence of observational or longitudinal human studies on thiothixene in published literature precludes drawing conclusions regarding the significance of toxic effects at therapeutic dosages.

Chemistry

Thiothixene is a tricyclic compound consisting of a thioxanthene core with a (4-methylpiperazin-1-yl)propylidene side chain.[30] Several methods for the synthesis of thiothixene are described in literature, which all rely on varying thioxanthone derivatives upon which the (4-methylpiperazin-1-yl)propylidene side chain is constructed.[2][16][31]

Wyatt et al. described the synthesis of thiothixene via four different routes, three of which originated from the previous findings from Muren et al. One method described the synthesis of thiothixene by acetylation of 9-lithio-N,N-dimethylthioxanthene-2-sulfonamide. After acetylation, a condensation reaction, and an amine exchange the intermediate ketone was obtained. This intermediate was then converted into E- and Z-thiothixene through reduction with NaBH4, followed by dehydration using POCl3-pyridine.[2][31]

Another method described by Muren et al. was performed using N,N-dimethylsulfamoyl-Z-thioxanthen-9-one as starting material. The introduction of the piperazinylpropylidene side chain was performed by a Wittig reaction. Following this, the methylation of the piperazinylpropylidene side chain was executed using various alkylating agents, yielding E- and Z-thiothixene.[31]  

The last method described by Wyatt et al, adapted from the study described by Muren and Bloom, used potassium benzenethiolate and 2-bromo-5-dimethylsulfamoylbenzoic acid as starting material. The resulting acid was treated with copper and PPA to form the thioxanthone intermediate. This ketone intermediate was then treated with the addition of the piperazinylpropylidene side chain and the loss of a water molecule to form Z- and E-Thiothixene.[2]  

The fourth method originating from D.C Hobbs involved condensing thiophenol with 2-chloro-5-dimethylsulfamoylbenzoic acid in an alkaline DMF solution at 130–140 °C. After a ring closure reaction with polyphosphoric acid at 70 °C, the ketone intermediate (N,N-dimethylsulfamoyl-Z-thioxanthen-9-one) was obtained. A wittig reaction was employed to connect the intermediate with the piperazinylpropylidene side chain, leading to the formation of both Z- and E-thiothixene isomers.[16][32]

References

  1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
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Comune in Piedmont, ItalySan Maurizio d'OpaglioComuneComune di San Maurizio d'OpaglioSan Maurizio d'OpaglioLocation of San Maurizio d'Opaglio San Maurizio d'OpaglioLocation of San Maurizio d'Opaglio in ItalyShow map of ItalySan Maurizio d'OpaglioSan Maurizio d'Opaglio (Piedmont)Show map of PiedmontCoordinates: 45°46′N 8°23′E / 45.767°N 8.383°E / 45.767; 8.383CountryItalyRegionPiedmontProvinceNovara (NO)FrazioniSazza, Pascolo, Lagna, Alpiolo, Opagliolo, Bacchior...

 

 

FA Charity Shield 1991

Voce principale: FA Community Shield. FA Charity Shield 1991Supercoppa d'Inghilterra 1991 Competizione FA Community Shield Sport Calcio Edizione 69ª Organizzatore The FA Date 10 agosto 1991 Luogo  Inghilterra Risultati Vincitore Arsenal eTottenham(8º e 7º titolo) Statistiche Incontri disputati 1 Gol segnati 0 (0 per incontro) Pubblico 65 483 (65 483 per incontro) Cronologia della competizione 1990 1992 Manuale Lo FA Charity Shield 1991, noto in italiano anche come Supe...

 

 

George W. Houk

American politician George Washington HoukMember of the U.S. House of Representativesfrom Ohio's 3rd districtIn officeMarch 4, 1891 – February 9, 1894Preceded byElihu S. WilliamsSucceeded byPaul J. SorgMember of the Ohio House of Representativesfrom the Montgomery County districtIn officeJanuary 5, 1852 – January 1, 1854Serving with Daniel BeckelPreceded byThomas DoddsJohn E. ThomsSucceeded byWilliam GoudyMarcus T. Parrott Personal details...

Prefectures in France

Governmental subdivision in France Map of the prefectures in France with their INSEE number In France, a prefecture (French: préfecture, pronounced [pʁefɛktyʁ] ⓘ) may be:[1][2] the chef-lieu de département, the commune in which the administration of a department is located; the chef-lieu de région, the commune in which the administration of a region is located; the jurisdiction of a prefecture; the official residence or headquarters of a prefect. Although the a...

 

 

WOHF

Radio station in Bellevue, Ohio WOHFBellevue, OhioBroadcast areaSandusky/Port ClintonLake Erie IslandsFrequency92.1 MHzBranding92.1 The WolfProgrammingLanguage(s)EnglishFormatClassic hitsAffiliationsABC News RadioOhio State Sports NetworkUnited Stations Radio NetworksWestwood OneOwnershipOwnerBAS Broadcasting, Inc.(BAS Broadcasting, Inc.)Sister stationsWCPZWFRO-FMWLECWMJKHistoryFirst air dateApril 4, 1973 (1973-04-04)Former call signsWNRR (1973–2003)Technical information[...