Thiethylperazine targets dopamine D2 receptors and histamine H1 receptors. It blocks postsynaptic dopamine D2 receptors in the medullary chemoreceptor trigger zone (CTZ), thereby decreasing stimulation of the vomiting center in the brain. Peripherally, it also acts as a dopamine antagonist. The compound is a selective ABCC1 activator. By activating ABCC1, Thiethylperazine reduces amyloid-β (Aβ) load, suggesting potential for Alzheimer's disease research.

Antibiotic action (vancomycin) is enhanced by thiethylperazine at as little as 2 μg/mL. With MIC values of 8 μg/mL and 16 μg/mL, respectively, Thietylperazine can inhibit isolates of vancomycin-susceptible Enterococcus faecalis ATCC 29212, vancomycin-resistant Enterococcus faecalis ATCC 51299, and vancomycin-resistant Enterococcus faecalis (VREF). mL and 8 μg/mL [3].

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Thiethylperazine demonstrates in vitro activity as a dopamine D2 receptor and histamine H1 receptor antagonist. As an ABCC1 activator, it reduces amyloid-β (Aβ) load in cellular models. The compound's antibacterial activity has also been observed in vitro. Specific in vitro data, including binding affinities (Ki values), IC50 values, and detailed assay conditions, are not extensively provided in the available literature. The compound's antiemetic activity is well-established through its D2 receptor antagonism in the CTZ.

In young APP/PS1 mice, thiethylperazine (3 mg/kg; intramuscular injection; twice daily; for 30 days) dramatically decreased Aβ42 levels [2].

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Thiethylperazine demonstrates in vivo antiemetic activity through its blockade of dopamine D2 receptors in the medullary chemoreceptor trigger zone. It is particularly useful in treating nausea and vomiting associated with anesthesia, mildly emetic cancer chemotherapy agents, radiation therapy, and toxins. In mice, Thiethylperazine reduces amyloid-β (Aβ) load through its ABCC1 activating properties. This suggests potential for Alzheimer's disease research. Specific dosing regimens, routes of administration, and detailed efficacy data are not extensively provided in the available literature.

In vitro receptor binding assays for Thiethylperazine involve measuring affinity for dopamine D2 and histamine H1 receptors. Membrane preparations from cells expressing human recombinant D2 or H1 receptors are incubated with radiolabeled ligands (e.g., [³H]spiperone for D2, [³H]mepyramine for H1) and varying concentrations of Thiethylperazine (typically 0.1-1000 nM) at room temperature for 60-120 minutes. Non-specific binding is determined in the presence of excess unlabeled ligand. Bound radioactivity is collected by filtration onto glass fiber filters and quantified by scintillation counting. Ki values are calculated from competition curves.

For in vitro cell-based assays, cells expressing dopamine D2 receptors or histamine H1 receptors are cultured in appropriate medium. Cells are treated with Thiethylperazine at various concentrations (typically 0.1-1000 nM). Receptor activation is measured by assessing downstream signaling pathways (e.g., cAMP accumulation for D2, calcium mobilization for H1). For ABCC1 activation, cells expressing ABCC1 are treated with Thiethylperazine, and transporter activity is measured by assessing efflux of fluorescent substrates or by measuring intracellular Aβ levels. Cell viability is assessed using MTT or similar assays.

Animal/Disease Models: juvenile Aβ precursor protein (APPswe) and mutant presenilin-1 (PS1) (APP/PS1) mice [2]
Doses: 3 mg/kg
Route of Administration: intramuscularinjection; twice (two times) daily; for 30 Day
Experimental Results: Aβ42 levels were Dramatically diminished in APP/PS1 mice.

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In vivo animal studies for Thiethylperazine include models of emesis (e.g., cisplatin-induced emesis in ferrets or dogs) to assess antiemetic activity. The compound is administered orally or intravenously at doses determined from pharmacokinetic studies. Emesis frequency and severity are recorded. For Alzheimer's disease research, transgenic mouse models of amyloid pathology (e.g., APP/PS1 mice) are used. Thiethylperazine is administered orally or intraperitoneally for several weeks. Aβ load in brain tissues is measured by ELISA or immunohistochemistry. Behavioral tests (e.g., Morris water maze) assess cognitive function.

Absorption, Distribution and Excretion
Thietapirazine is excreted in the urine. Approximately half of the metabolites of commonly used phenothiazines are found in the urine, and the remainder in the feces. Many metabolites can still be detected in the urine 6 months after discontinuation of these drugs. /Phenothiazines/ Phenothiazine sedatives cross the placenta rapidly. These drugs have been detected in the urine and tissues of newborns from treated mothers for many years, but only recently have extremely low concentrations in the blood of both mother and fetus been detected… /Phenothiazines/ Metabolism/ Metabolites In principle, the metabolites of thioridazine appear to be similar to those of thioridazine. Most of the drug is secreted into the bile as glucuronide. …Metabolism… is an oxidation process mediated primarily by genetically controlled hepatic microsomal oxidases and binding processes. /Phenothiazines/

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Thiethylperazine is orally active and can be administered orally or intravenously. The compound is a phenothiazine derivative with good oral bioavailability. It is soluble in common organic solvents. Detailed pharmacokinetic parameters (absorption, distribution, metabolism, excretion, half-life, Cmax, Tmax, AUC) are not extensively characterized in the available literature. As a phenothiazine derivative, it would be expected to be extensively metabolized in the liver and have a relatively long half-life. The compound's ability to cross the blood-brain barrier is suggested by its central effects.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Based on the minimal excretion of other phenothiazine derivatives, occasional short-term use of thiamethoxam for nausea and vomiting poses minimal risk to breastfed infants. ◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk
Phenothiazine drugs can cause galactorrhea in 26% to 40% of female patients. Hyperprolactinemia appears to be the cause of galactorrhea. Hyperprolactinemia is caused by the drug blocking the action of dopamine in the tuberous-infundibular pathway.

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Protein binding rate
60%Interactions
/Interactions with the following drugs/...Guetethidine (blocks antihypertensive effects); Morphine (enhances sedation); Pethidine (exacerbates respiratory depression); Barbiturates and other central nervous system depressants, including alcohol (enhances sedation or prolongs post-anesthesia sleep time).../Malate and maleate/
/Interactions with the following drugs/...Levodopa (reduces absorption and efficacy); Anticonvulsants (lowers the epileptic threshold); Procarbazine (enhances behavioral abnormalities). /Malate and maleate/

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Thiethylperazine is generally well-tolerated at therapeutic doses. As a phenothiazine derivative, it may have side effects including extrapyramidal symptoms, sedation, and anticholinergic effects. The compound's dopamine D2 receptor antagonism may cause parkinsonian-like symptoms at higher doses. Its H1 receptor antagonism may cause sedation. Specific toxicity data, including acute toxicity, repeated-dose toxicity, and genotoxicity, are not extensively provided in the available literature. Standard toxicology assessments would be required for therapeutic development.

[1]. Case-control study of teratogenic potential of thiethylperazine, an anti-emetic drug. BJOG. 2003 May;110(5):497-9.

[2]. Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest. 2011 Oct;121(10):3924-31.

[3]. Enhancement of vancomycin activity by phenothiazines against vancomycin-resistant Enterococcus faecium in vitro. Basic Clin Pharmacol Toxicol. 2010 Aug;107(2):676-9.

Thietiperazine is a phenothiazine compound with a piperazine group substituted at the 2-position with an ethylthio group. It possesses various pharmacological activities, including function as a phenothiazine antipsychotic, histamine antagonist, muscarinic receptor antagonist, serotonin receptor antagonist, dopamine receptor antagonist, and antiemetic. It belongs to the phenothiazine and N-methylpiperazine classes and is functionally related to piperazine compounds. Thietiperazine is a dopamine antagonist, particularly suitable for treating nausea and vomiting caused by anesthesia, mildly emetogenic chemotherapy drugs, radiotherapy, and toxins. This piperazine-type phenothiazine does not prevent vertigo or motion sickness. (Excerpt from JAMA Drug Evaluation Yearbook, 1994, p. 457)
Thiamethoxam is a piperazine-phenothiazine derivative and also a dopamine antagonist, used as an antiemetic. Thietiperazine blocks postsynaptic dopamine 2 (D2) receptors in the medullary chemoreceptor trigger zone (CTZ), thereby reducing stimulation of the vomiting center in the brain. Peripherally, thiaperrazine blocks the vagus nerve in the gastrointestinal tract. In addition, the drug exhibits antagonistic activity mediated by muscarinic receptors, H1 receptors, and α1 receptors. Thietiperazine is a dopamine antagonist, particularly suitable for treating nausea and vomiting induced by anesthesia, mildly emetogenic chemotherapy drugs for cancer, radiotherapy, and toxins. This piperazine-phenothiazine drug does not prevent vertigo or motion sickness. (From JAMA Drug Evaluation Yearbook, 1994, p. 457)
Drug Indications
For the treatment or relief of nausea and vomiting.
Mechanism of Action
Thietiperazine is an antagonist of dopamine receptors types 1, 2, and 4, 5-HT receptors types 2A and 2C, muscarinic receptors types 1 through 5, α1 receptors, and histamine H1 receptors. The antipsychotic effect of thiamethoxam is due to its antagonism of dopamine and 5-HT2 receptors, with higher activity against 5-HT2 receptors than against dopamine type 2 receptors. This may explain its lack of extrapyramidal side effects. Thietiperazine does not appear to block dopamine in the tuberous-infundibular bundle, which explains its lower incidence of hyperprolactinemia compared to typical antipsychotics or risperidone. Thietiperazine also antagonizes muscarinic receptors, H1 receptors, and α1 receptors.
An adenylate cyclase exists in the limbic system and caudate nucleus, which can be specifically activated by dopamine. …Activation of this enzyme…is blocked by…phenothiazine drugs. ...The therapeutic effects and side effects may be related to the inhibition of dopamine-activated adenylate cyclase. Phenothiazines...Phenothiazines block dopamine receptors, increasing dopamine turnover in the striatum. This increase in turnover is considered a result of neural feedback mechanisms. ...The firing activity of identified dopaminergic neurons in the substantia nigra and ventral tegmentum is increased by the antipsychotic drug phenothiazines. Phenothiazines

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Therapeutic Uses
Antiemetics; Dopamine antagonists
Veterinary Experimental Applications: The effect of thiamethoxam on vestibular nystagmus in rabbits was studied. Nystagmus was induced by torsional oscillation. Thiamethoxam showed a significant inhibitory effect, but its intensity and duration of action were weaker than those of cinnarizine and sulpiride.
Experimental Applications (Veterinary): Dogs fed 0.4 kg of dog food were subsequently given an intramuscular injection of 0.86 mg/kg thiamethoxam and irradiated using a ⁶⁰CO remote radiotherapy device. The radiation dose (ED50) that caused vomiting in 50% of control dogs was 170 rad. The ED50 for thiazide increases to 320 rad. Thiahiazide is a phenothiazine antiemetic that effectively relieves nausea and vomiting from various causes. It may also be effective in treating dizziness. /Maleates/ For more complete data on the therapeutic uses of thiazides (12 in total), please visit the HSDB record page.

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Drug Warnings
Contraindicated in pregnant women and children under 12 years of age. Other contraindications and side effects are the same as with other phenothiazines. Maleates: These drugs should be used with caution in patients with severe liver disease and epilepsy, as well as in elderly patients. Phenothiazine antiemetics: Phenothiazines should be used with extreme caution, or even contraindicated, in patients with untreated epilepsy and in patients who are withdrawing from central nervous system depressants (such as alcohol, barbiturates, and benzodiazepines). They can be used in patients with epilepsy if the dose is gradually increased while maintaining anticonvulsant therapy. /Phenothiazines/
...When using phenothiazines to treat nausea and vomiting, the same precautions should be taken as when using potent analgesics to treat pain, as they may mask diagnostic symptoms of acute surgical conditions or neurological syndromes. /Phenothiazines/
For more complete data on drug warnings for ethylthiopiperazine (31 in total), please visit the HSDB records page.

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Pharmacodynamics
Thietiperazine is an atypical antipsychotic used to treat negative and positive symptoms of schizophrenia, acute mania and agitation in bipolar disorder, and psychotic symptoms of dementia. Future uses may include the treatment of severe behavioral disorders in obsessive-compulsive disorder and autism. Thietiperazine is structurally and pharmacologically similar to clozapine and binds to α1 receptors, dopamine receptors, histamine H1 receptors, muscarinic receptors, and serotonin type 2 (5-HT2) receptors.

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Thiethylperazine is a piperazine phenothiazine derivative and a dopamine antagonist used as an antiemetic. It blocks postsynaptic dopamine D2 receptors in the medullary chemoreceptor trigger zone, decreasing stimulation of the vomiting center. The compound is also a histamine H1 receptor antagonist and a selective ABCC1 activator that reduces amyloid-β (Aβ) load in mice. It has anti-emetic, antibacterial, and potential neuroprotective activities. Thiethylperazine is used for relieving vertigo and may have applications in Alzheimer's and Parkinson's disease research. No approved therapeutic status is reported for these new indications.

C22H29N3S2

399.615

399.18

1420-55-9

Thiethylperazine dimaleate;1179-69-7

5440

Light brown to gray solid powder

1.24g/cm3

559.8ºC at 760mmHg

62-64°

292.4ºC

1.5605 (estimate)

4.979

0

5

6

27

455

0

XCTYLCDETUVOIP-UHFFFAOYSA-N

InChI=1S/C22H29N3S2/c1-3-26-18-9-10-22-20(17-18)25(19-7-4-5-8-21(19)27-22)12-6-11-24-15-13-23(2)14-16-24/h4-5,7-10,17H,3,6,11-16H2,1-2H3

2-ethylsulfanyl-10-[3-(4-methylpiperazin-1-yl)propyl]phenothiazine

Norzine; Torecan; Thiethylperazine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~250.24 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)