Tiotixene

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]

Tiotixene

Clinical data
Trade names	Navane
Other names	Thiothixene (USAN US)
AHFS/Drugs.com	Monograph
MedlinePlus	a682867
Pregnancy category	AU: B1
Routes of administration	By mouth
Drug class	Typical antipsychotic
ATC code	N05AF04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances)[1] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	~100%
Metabolism	Hepatic
Elimination half-life	10–20 hours
Excretion	Gastrointernal tract, faeces
Identifiers
IUPAC name (9Z)-N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene]-9H-thioxanthene-2-sulfonamide
CAS Number	3313-26-6 Y
PubChem CID	941651
IUPHAR/BPS	212
DrugBank	DB01623 Y
ChemSpider	819430 Y
UNII	7318FJ13YJ
KEGG	D00374
ChEMBL	ChEMBL1201 Y
CompTox Dashboard (EPA)	DTXSID2091542
ECHA InfoCard	100.233.356
Chemical and physical data
Formula	C23H29N3O2S2
Molar mass	443.62 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=S(=O)(N(C)C)c2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN4CCN(C)CC4
InChI 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- Y Key:GFBKORZTTCHDGY-UWVJOHFNSA-N Y
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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 Parkinsonism 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.

Efferocytosis

Thiothixene stimulates macrophages to clear pathogenic cells by inducing arginase 1 and continual efferocytosis.^[27]

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.^[28][29]

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.^[30] 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.^[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]

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][32]

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.^[32]  

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][33]