Chemistry:Tiotixene

From HandWiki

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.[1] Beyond its primary indication, it can exhibit a variety of effects common to neuroleptic drugs including anxiolytic, anti-depressive, and anti-aggressive properties.[2]

The drug was first synthesized and marketed in 1967 under the pharmaceutical company Pfizer.[1][3][4][5] While the usage of the drug has declined in recent decades, the drug continues to be manufactured and prescribed in the US and Canada.[5]

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.[6] The drug regulates behaviour and thoughts, and can also exhibit an anti-depressive effect.[2][7]  

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.[8][9] Less frequently encountered side effects are drug-induced movement disorders such as Parkinsonism and tardive dyskinesia.[10][11]

The results of various dose-response studies (10–60 mg) indicate a stimulating effect at lower doses, which diminishes as higher doses are administered.[12] Overall, the efficacy of thiothixene when compared to other antipsychotic drugs was evaluated to be at least as effective regardless of the optimum dosage.[12][13][14]

Pharmacology

Pharmacokinetics

As common with tricyclic psychotherapeutic agents, tiotixene is rapidly and extensively absorbed.[15] Peak serum concentration of the drug is achieved after 1–3 hours.[16] After absorption, the compound and its metabolites are spread widely throughout the body.  

The drug's metabolism proceeds rapidly and primarily in the liver.[1][15] Although N-demethyltiotixene was identified as its major metabolite, the metabolic mechanisms remain elusive.[1][17] After metabolism, most of the material is excreted through the faeces.[15]

Pharmacodynamics

Site Ki (nM) Species Ref
NET 30,200 Human [18][19]
DAT 3,630 Human [18][19]
5-HT1A 410–912 Human [18][20][19]
5-HT1B 151 Human [18]
5-HT1D 659 Human [18]
5-HT1E >10,000 Human [18]
5-HT2A 50–89 Human [20][19]
5-HT2C 1,350–1,400 Human [20][19]
5-HT3 1,860 Human [18][19]
5-HT5A 361 Human [18]
5-HT6 208–320 Human [18][20][19]
5-HT7 15.5 Human [18][20][19]
α1 19 ND [19]
  α1A 11–12 Human [18][20]
  α1B 35 Human [18]
α2 95 ND [19]
  α2A 80 Human [18][20]
  α2B 50 Human [18][20]
  α2C 52 Human [18][20]
β1 >10,000 Human [18]
β2 >10,000 Human [18]
D1 51–339 Human [18][19]
D2 0.03–1.4 Human [18][20][21]
D3 0.3–186 Human [21][19]
D4 203–363 Human [18][19]
D4.2 410–685 Human [21]
D5 261 Human [18]
H1 4.0–12 Human [18][20][22]
H2 411 Human [18]
H3 1,336 Guinea pig [18]
H4 >10,000 Human [18]
mACh 3,310 ND [19]
  M1 ≥2,820 Human [18][19]
  M2 ≥2,450 Human [18][19]
  M3 ≥5,750 Human [18][20][19]
  M4 >10,000 Human [18]
  M5 5,376 Human [18]
σ 1,780 ND [19]
Values are Ki (nM). The smaller the value,
the more strongly the drug binds to the site.

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.[23] 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.[23][24] This reduction of abnormal neurotransmission activity tends to alleviate the psychotic indications associated with schizophrenia.[25]

Tiotixene acts primarily as a highly potent antagonist of the dopamine D2 and D3 receptors (subnanomolar affinity).[18] 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).[18] It does not have any anticholinergic activity.[18] Antagonism of the D2 receptor is thought to be responsible for the antipsychotic effects of tiotixene.

Efferocytosis

Thiothixene stimulates macrophages to clear pathogenic cells by inducing arginase 1 and continual efferocytosis.[26]

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.[1][15][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.[1][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.[1]  

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.[15][32]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Thiothixene". Analytical Profiles of Drug Substances. 18. Academic Press. 1990-01-01. pp. 527–565. doi:10.1016/s0099-5428(08)60680-2. ISBN 978-0-12-260818-6. 
  2. ↑ 2.0 2.1 "Before Prozac: The troubled history of mood disorders in psychiatry" (in en). The Journal of Clinical Investigation 119 (8): 2117. 2009-08-03. doi:10.1172/JCI40286. ISSN 0021-9738. 
  3. ↑ "A Double-Edged Sword: Thioxanthenes Act on Both the Mind and the Microbiome". Molecules 27 (1): 196. December 2021. doi:10.3390/molecules27010196. PMID 35011432. 
  4. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 3214–. ISBN 978-0-8155-1856-3. https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA3214. 
  5. ↑ 5.0 5.1 "Chlorpromazine versus piperacetazine for schizophrenia". The Cochrane Database of Systematic Reviews 10 (10): CD011709. October 2018. doi:10.1002/14651858.CD012790. PMID 30378678. 
  6. ↑ "Injectable long-term control-released in situ gels of hydrochloric thiothixene for the treatment of schizophrenia: preparation, in vitro and in vivo evaluation". International Journal of Pharmaceutics 469 (1): 23–30. July 2014. doi:10.1016/j.ijpharm.2014.04.044. PMID 24751344. 
  7. ↑ "Major tranquillisers used as antidepressants. A review". Journal of Affective Disorders 4 (3): 173–193. September 1982. doi:10.1016/0165-0327(82)90002-7. PMID 6127357. 
  8. ↑ "Experiences with thiothixene". The British Journal of Psychiatry 114 (506): 123. January 1968. doi:10.1192/bjp.114.506.123. PMID 5636080. 
  9. ↑ "Comparison of efficacy of zotepine and thiothixene in schizophrenia in a double-blind study". Pharmacopsychiatry 20 (1 Spec No): 38–46. February 1987. doi:10.1055/s-2007-1017128. PMID 2883680. 
  10. ↑ "Broad-spectrum screening of psychotherapeutic drugs: thiothixene as an antipsychotic and antidepressant". Clinical Pharmacology and Therapeutics 10 (1): 36–43. January 1969. doi:10.1002/cpt196910136. PMID 4884295. 
  11. ↑ "Tardive dyskinesia and steady-state serum levels of thiothixene". Archives of General Psychiatry 44 (10): 913–915. October 1987. doi:10.1001/archpsyc.1987.01800220085012. PMID 2889439. 
  12. ↑ 12.0 12.1 "The dual action of thiothixene". Archives of General Psychiatry 29 (2): 222–225. August 1973. doi:10.1001/archpsyc.1973.04200020056007. PMID 4741513. 
  13. ↑ "A preliminary evaluation of P-4657B: a thioxanthene derivative". The American Journal of Psychiatry 123 (3): 345–346. September 1966. doi:10.1176/ajp.123.3.345. PMID 5921658. 
  14. ↑ "Thiothixene versus trifluoperazine in newly-admitted schizophrenic patients". Current Therapeutic Research, Clinical and Experimental 8 (11): 509–514. November 1966. PMID 4962777. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "Metabolism of thiothixene". Journal of Pharmaceutical Sciences 57 (1): 105–111. January 1968. doi:10.1002/jps.2600570121. PMID 5652108. 
  16. ↑ "Pharmacokinetics of thiothixene in man". Clinical Pharmacology and Therapeutics 16 (3): 473–478. September 1974. doi:10.1002/cpt1974163part1473. PMID 4415039. 
  17. ↑ "The effect of paroxetine on thiothixene pharmacokinetics". Journal of Clinical Pharmacy and Therapeutics 22 (3): 221–226. June 1997. doi:10.1046/j.1365-2710.1997.95175951.x. PMID 9447478. 
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 18.13 18.14 18.15 18.16 18.17 18.18 18.19 18.20 18.21 18.22 18.23 18.24 18.25 18.26 18.27 18.28 18.29 18.30 18.31 18.32 Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  19. ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 Cite error: Invalid <ref> tag; no text was provided for refs named pmid16082416
  20. ↑ 20.00 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 20.10 20.11 "H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs". Neuropsychopharmacology 28 (3): 519–526. March 2003. doi:10.1038/sj.npp.1300027. PMID 12629531. 
  21. ↑ 21.0 21.1 21.2 "Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist". The Journal of Pharmacology and Experimental Therapeutics 315 (3): 1278–1287. December 2005. doi:10.1124/jpet.105.092155. PMID 16135699. 
  22. ↑ "Histamine H1 receptors in human brain labelled with [3H]doxepin". Brain Research 304 (1): 1–7. June 1984. doi:10.1016/0006-8993(84)90856-4. PMID 6146381. 
  23. ↑ 23.0 23.1 "Deep learning applications for the accurate identification of low-transcriptional activity drugs and their mechanism of actions". Pharmacological Research 180. June 2022. doi:10.1016/j.phrs.2022.106225. PMID 35452801. 
  24. ↑ "Psychotic Disorders, Definition, Sign and Symptoms, Antipsychotic Drugs, Mechanism of Action, Pharmacokinetics & Pharmacodynamics with Side Effects & Adverse Drug Reactions: Updated Systematic Review Article". Journal of Drug Delivery and Therapeutics 10 (1): 163–172. January 2020. doi:10.22270/jddt.v10i1.3865. ISSN 2250-1177. http://jddtonline.info/index.php/jddt/article/view/3865. 
  25. ↑ "Schizophrenia: overview and treatment options". P & T 39 (9): 638–645. September 2014. PMID 25210417. 
  26. ↑ "The antipsychotic drug thiothixene stimulates macrophages to clear pathogenic cells by inducing arginase 1 and continual efferocytosis | Science Signaling". 2025-04-09. doi:10.1126/scisignal.ads6584. https://www.science.org/doi/10.1126/scisignal.ads6584. 
  27. ↑ "Thiothixene (Navane)" (in en). Clinical Pharmacology & Therapeutics 9 (2): 282–284. March 1968. doi:10.1002/cpt196892282. ISSN 0009-9236. 
  28. ↑ "Cytotoxic effects of neuroleptic drugs". Psychopharmacology 91 (2): 182–188. February 1987. doi:10.1007/BF00217059. PMID 2883697. 
  29. ↑ "The toxicity of thioxanthene neuroleptics to isolated rat liver cells". Proceedings of the Society for Experimental Biology and Medicine 150 (2): 385–389. November 1975. doi:10.3181/00379727-150-39041. PMID 1208553. 
  30. ↑ "Density functional theory study of structural and electronic properties of trans and cis structures of thiothixene as a nano-drug". Journal of Molecular Modeling 23 (12). November 2017. doi:10.1007/s00894-017-3522-6. PMID 29177682. 
  31. ↑ 31.0 31.1 31.2 "Thioxanthene psychopharmacological agents. II. 9-(3-aminopropylidene)-N,N-dimethylthioxanthene-2-sulfonamides". Journal of Medicinal Chemistry 13 (1): 17–23. January 1970. doi:10.1021/jm00295a005. PMID 5412109. 
  32. ↑ "A review on synthesis of FDA-approved antipsychotic drugs". Tetrahedron 138. May 2023. doi:10.1016/j.tet.2023.133430. ISSN 0040-4020. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Tiotixene&oldid=4029089"