Zotepine exhibits multiple antagonistic profiles and strong affinities to α1-adrenergic, α₂-adrenergic, Dopamine D₂, Histamine H1, Muscarinic, 5-HT_1A, 5-HT_1D, 5-HT_2A, and 5-HT_2C receptors, with K_ds of 7.3, 180, 8, 3.3, 330, 280, 80, 2.6, 3.2 nM, respectively[1].

Zotepine (1-3 mg/kg; a single i.p.) dose-dependently raises noradrenaline, dopamine, glutamate release, and GABA levels without changing 5-HT levels in the medial prefrontal cortex of rats[2].

Male Sprague-Dawley rats (250-300 g)
1, 3 mg/kg
A single i.p.

Absorption, Distribution and Excretion
Preclinical pharmacokinetic studies showed that when zotepine was administered at doses of 25-100 mg, plasma concentrations increased in a dose-dependent manner, with a time to peak concentration (tmax) of 2-4 hours and a peak plasma concentration (Cmax) of 6.9-19.6 ng/ml. After reaching peak concentration, plasma concentrations declined slowly. Preclinical studies indicated that after oral administration of zotepine, the drug was rapidly and almost completely absorbed from the gastrointestinal tract. The parent drug and its metabolites were rapidly distributed to tissues. Only a small amount of parent drug zotepine was excreted in the urine; the parent drug and its metabolites were primarily excreted in the feces via bile. The apparent volume of distribution of zotepine was 109 L/kg. The apparent oral clearance of zotepine was 4.6 mg/h·kg. Metabolism/Metabolites Zotepine is well metabolized in vivo, undergoing extensive first-pass metabolism to produce the metabolite norzotepine and several inactive metabolites. The main enzymes involved in the metabolism of zotepine are CYP1A2 and CYP3A4. Some major metabolic pathways include N-demethylation and oxidation of the N or S atom, hydroxylation of the aromatic ring, and subsequent conjugation reactions. Known metabolites of zotepine include 3-hydroxyzotepine, zotepine N-oxide, zotepine-oxide, norzotepine, and 2-hydroxyzotepine. The biological half-life of zotepine has been reported to be 21 hours.

Protein Binding

Zothipin and its main active metabolite, norzothipin, have a plasma protein binding rate of 97% of the administered dose.

[1]. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci. 2000 Nov 24;68(1):29-39.

[2]. Effects of zotepine on extracellular levels of monoamine, GABA and glutamate in rat prefrontal cortex. Br J Pharmacol. 2009 Jun;157(4):656-65.

Zotepine is a dibenzothiophene compound and a tertiary amine compound. It is both an alpha-adrenergic and a serotonergic drug, belonging to the second generation of antipsychotics. Zotepine, with the chemical formula 2-chloro-11-(2-dimethylaminoethoxy)-dibenzothiophene, is a neuroleptic. It was designed and synthesized by Fujisawa Pharmaceutical Co., Ltd. Since the 1980s, it has been used as an antipsychotic in Japan, India, and parts of Europe, including the UK and Germany. Zotepine has never been approved by the U.S. Food and Drug Administration (FDA). In 1993, it was classified as an inactive pharmaceutical ingredient (Class I, Type II). In 1995, the FDA investigated the manufacturing process of zotepine tablets in Germany, but its status remained inactive. In 2016, when the FDA re-evaluated antipsychotics, zotepine did not meet the threshold effect for further research. By 2015, the European Medicines Agency (EMA) had conducted pharmacovigilance studies on it. Potential treatment for acute renal failure.

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Drug Indications
Zotepine, like other atypical antipsychotics, is considered a first-line treatment for newly diagnosed schizophrenia. It is generally considered the preferred treatment for acute schizophrenic episodes when communication with the patient is impossible. Zotepine, as an atypical antipsychotic, is used to treat patients who cannot tolerate the side effects of conventional antipsychotics, or to treat patients with relapsed and poorly controlled schizophrenia. It is important to note that the above indications are all related to atypical antipsychotics. Zotepine has not yet been approved by the U.S. Food and Drug Administration (FDA), the Canadian Medicines Agency (EMA), or the European Medicines Agency (EMA), and studies have not shown any additional benefit compared to other approved atypical antipsychotics. Schizophrenia is a chronic and severe mental disorder that affects a patient's thinking, feelings, and behavior. It is typically characterized by blurred perception of reality, accompanied by hallucinations, delusions, and thought and motor disturbances.

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Mechanism of Action
Zotepine is a dopamine antagonist with high affinity for D1 and D2-like receptors. It exhibits potent antagonism against multiple serotonin receptors, such as 5-HT2a, 5-HT2c, 5-HT6, and 5-HT7. Zotepine's activity is also associated with the inhibition of norepinephrine reuptake and serotonergic activity. All these effects enable zotepine to improve negative and cognitive symptoms of schizophrenia.

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Pharmacodynamics
In preclinical studies, zotepine demonstrated stronger anti-serotonergic activity compared to other antipsychotics. It has also been reported to increase the seizure threshold of the amygdala. When the effects of zotepine were analyzed via electroencephalography, typical responses to less potent antipsychotics were observed. Zotepine is a sedative. After taking zotepine, patients showed improvements in numerical and complex reaction abilities. However, these effects are often accompanied by increased heart rate, elevated prolactin levels, and some typical antipsychotic side effects.

C18H18CLNOS

331.86

331.079

C, 65.15; H, 5.47; Cl, 10.68; N, 4.22; O, 4.82; S, 9.66

26615-21-4

5736

White to off-white solid powder

1.3±0.1 g/cm3

478.4±45.0 °C at 760 mmHg

90-91 °C

243.2±28.7 °C

0.0±1.2 mmHg at 25°C

1.656

6.57

0

3

4

22

401

0

CN(C)CCOC1=CC2=CC=CC=C2SC3=C1C=C(C=C3)Cl

HDOZVRUNCMBHFH-UHFFFAOYSA-N

InChI=1S/C18H18ClNOS/c1-20(2)9-10-21-16-11-13-5-3-4-6-17(13)22-18-8-7-14(19)12-15(16)18/h3-8,11-12H,9-10H2,1-2H3

2-(3-chlorobenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethylethanamine

Zotepine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: ~25 mg/mL (~75.3 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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