Tiotixene, or thiothixene, is a typical antipsychotic sold under the brand name Navane which is predominantly utilised to treat schizophrenia. Beyond its primary indication, it can exhibit a variety of effects common to neuroleptic drugs including anxiolytic, anti-depressive, and anti-aggressive properties.
The drug was first synthesized and marketed in 1967 under the pharmaceutical company Pfizer. While the usage of the drug has declined in recent decades, the drug continues to be manufactured and prescribed in the US and Canada. The drug regulates behaviour and thoughts, and can also exhibit an anti-depressive effect.
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. Less frequently encountered side effects are drug-induced movement disorders such as Parkinsonism and tardive dyskinesia.
The results of various dose-response studies (10–60 mg) indicate a stimulating effect at lower doses, which diminishes as higher doses are administered. Overall, the efficacy of thiothixene when compared to other antipsychotic drugs was evaluated to be at least as effective regardless of the optimum dosage.
Pharmacology
Pharmacokinetics
As common with tricyclic psychotherapeutic agents, tiotixene is rapidly and extensively absorbed. Peak serum concentration of the drug is achieved after 1–3 hours. After absorption, the compound and its metabolites are spread widely throughout the body.
The drug's metabolism proceeds rapidly and primarily in the liver. After metabolism, most of the material is excreted through the faeces.
|-
! Site !! K<sub>i</sub> (nM) !! Species !! Ref
|-
| || 3,162–3,878 || Human ||
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| || 30,200 || Human ||
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| D<sub>3</sub> || 0.3–186 || Human ||
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| H<sub>2</sub> || 411 || Human || 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. This reduction of abnormal neurotransmission activity tends to alleviate the psychotic indications associated with schizophrenia.
Tiotixene acts primarily as a highly potent antagonist of the dopamine D<sub>2</sub> and D<sub>3</sub> receptors (subnanomolar affinity).
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.
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. 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. 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.
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 NaBH<sub>4</sub>, followed by dehydration using POCl<sub>3</sub>-pyridine.