 | |
| Clinical data | |
|---|---|
| Trade names | Navane |
| Other names | Thiothixene (USANUS) |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682867 |
| Pregnancy category |
|
| Routes of administration | By mouth |
| Drug class | Typical antipsychotic |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | ~100% |
| Metabolism | Hepatic |
| Eliminationhalf-life | 10–20 hours |
| Excretion | Gastrointernal tract, faeces |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.233.356 |
| Chemical and physical data | |
| Formula | C23H29N3O2S2 |
| Molar mass | 443.62 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
Tiotixene, orthiothixene is atypical antipsychotic agent currently sold under the brand nameNavane which is predominantly utilised to treat acute and chronicschizophrenia.[2] Beyond its primaryindication, it can exhibit a variety of effects common toneuroleptic drugs includinganxiolytic, 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 thethioxanthene class, it is chemically related to other typical neuroleptic agents such aschlorprothixene,clopenthixol,flupenthixol, andzuclopenthixol. Tiotixene also shares structural similarities withthioproperazine andpipotiazine, which are members of thephenothiazine class.
Tiotixene is a widely used drug for the treatment of variouspsychiatric 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]
Theside effect profile is similar to related antipsychotic agents, displaying weight gain, mental distress, and inability to sit still. Other possible symptoms includeanticholinergic side effects such asinsomnia, blurred vision, and dry mouth.[9][10] Less frequently encountered side effects are drug-induced movement disorders such asParkinsonism andtardive 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]
As common withtricyclic psychotherapeutic agents, tiotixene is rapidly and extensively absorbed.[16] Peakserum concentration of the drug is achieved after 1–3 hours.[17] After absorption, the compound and itsmetabolites are spread widely throughout the body.
The drug'smetabolism proceeds rapidly and primarily in the liver.[2][16] AlthoughN-demethyltiotixene was identified as its major metabolite, the metabolic mechanisms remain elusive.[2][18] After metabolism, most of the material isexcreted through thefaeces.[16]
| 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. | |||
Tiotixene shares its mechanism with related thioxanthenes which are all fundamentally used to control schizophrenia. Their mechanism of action involves the inhibition of differentreceptors, including5-HT (serotonin),dopaminergic,histaminergic, andadrenergic receptors.[24] Blocking these receptors results in a reduction of synaptic levels of dopamine, serotonin, and otherneurotransmitters 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 potentantagonist of thedopamineD2 andD3 receptors (subnanomolaraffinity).[19] It is also an antagonist of thehistamineH1,α1-adrenergic, andserotonin5-HT7 receptors (low nanomolar affinity), as well as of various other receptors to a much lesser extent (lower affinity).[19] It does not have anyanticholinergic activity.[19] Antagonism of the D2 receptor is thought to be responsible for the antipsychotic effects of tiotixene.
Thiothixene stimulatesmacrophages to clear pathogenic cells by inducingarginase 1 and continualefferocytosis.[27]
Thiothixene has demonstrated toxicity in animal studies and isolated human tissue, displayingcytotoxic effects against various cell types. Observed toxic effects included growth inhibition of mousefibroblasts, inhibition ofprotein synthesis by humanglioma cells, and inhibition ofleukocyteDNA synthesis.[28][29]
Other compounds within the thioxanthene class have demonstratedhepatotoxicity in rodent experiments, and althoughanecdotal reports of thiothixene-induced liver failure exist, scientific data regarding the correlation lacks.[30] The absence ofobservational orlongitudinal human studies on thiothixene in published literature precludes drawing conclusions regarding the significance of toxic effects at therapeutic dosages.
Thiothixene is a tricyclic compound consisting of a thioxanthene core with a (4-methylpiperazin-1-yl)propylidene side chain.[31] 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][32]
Wyattet al. described the synthesis of thiothixene via four different routes, three of which originated from the previous findings from Murenet al. One method described the synthesis of thiothixene byacetylation 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 intoE- andZ-thiothixene throughreduction with NaBH4, followed bydehydration using POCl3-pyridine.[2][32]
Another method described by Murenet al. was performed usingN,N-dimethylsulfamoyl-Z-thioxanthen-9-one as starting material. The introduction of the piperazinylpropylidene side chain was performed by aWittig reaction. Following this, themethylation of the piperazinylpropylidene side chain was executed using variousalkylating agents, yieldingE- andZ-thiothixene.[32]
The last method described by Wyattet 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 formZ- andE-Thiothixene.[2]
The fourth method originating from D.C Hobbs involved condensing thiophenol with 2-chloro-5-dimethylsulfamoylbenzoic acid in an alkalineDMF 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 bothZ- andE-thiothixene isomers.[16][33]
