Identification
- Generic Name
- Zotepine
- DrugBank Accession Number
- DB09225
- Background
Zotepine, with the formula (2-chloro-11-(2-dimethyl-amino-ethoxy)-dibenzo thiepin, is a neuroleptic drug. It was designed and synthesized by Fujisawa Pharmaceutical Co Ltd.1 It has been used as an antipsychotic in Japan, India and some places in Europe like UK and Germany since 1980's.2 Zotepine was never approved by the FDA. In 1993, it was classified as inactive drug substance (Status I, Type II) and in 1995 the FDA studied the manufacturing procedures of Zotepine tablets in Germany, but the status remained inactive.9 When the analysis of antipsychotics was retaken in 2016 by the FDA, zotepine did not reach the threshold effect to be further studied.10. In the EMA, by 2015 it was under pharmacovigilance studies for the potential treatment of acute renal failure.11
- Type
- Small Molecule
- Groups
- Approved, Investigational, Withdrawn
- Structure
Structure for Zotepine (DB09225)
- Weight
- Average: 331.86
Monoisotopic: 331.0797631 - Chemical Formula
- C18H18ClNOS
- Synonyms
- Zotepina
- Zotepine
Pharmacology
- Indication
Zotepine, like other atypical antipsychotics, is considered as the first-line treatment in newly diagnosed schizophrenia. It is usually thought to be an option of choice for managing acute schizophrenic episodes when discussion with the patient is not possible. Zotepine, as an atypical antipsychotic, is used in patients who are suffering unacceptable side effects from conventional antipsychotics or in relapse patients that were inadequately controlled.7
It is important to consider that the indications stated above are related to atypical antipsychotics, that zotepine is not currently FDA, Canada or EMA approved and that studies have not shown any additional benefit when compared with other approved atypical antipsychotics.2
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels and behaves. It is usually marked for a loose reality perspective delineated by hallucinations, delusions and thought and movement disorders.12
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In preclinical studies, zotepine is characterized by the presence of a strong antiserotonergic activity when compared with other neuroleptic drugs. It has also been reported to present elevations in the seizure threshold in the amygdaloid nucleus.1 When zotepine's effects were analyzed by electroencephalography, it was noted a typical response of a low-potency neuroleptics of the sedative type. Administration of zotepine has shown improvements in numerical movements and complex reaction. These effects tend to be accompanied by increases in pulse rate, increase in prolactin levels and some typical neuroleptic side effects.3,4
- Mechanism of action
Zotepine is a dopamine antagonist that has a high affinity for D1- and D2-like receptors. It presents a strong antagonism for several serotonin receptors, such as 5-HT2a, 5-HT2c, 5-HT6 and 5-HT7. Zotepine activities are also related to the inhibition of noradrenaline reuptake and serotonergic activity. All these effects allow zotepine to improve the negative and cognitive symptoms of schizophrenia.8
Target Actions Organism AD(1) dopamine receptor antagonistHumans ADopamine D2 receptor antagonistHumans A5-hydroxytryptamine receptor 2A antagonistHumans A5-hydroxytryptamine receptor 7 antagonistHumans ASodium-dependent noradrenaline transporter antagonistHumans ASodium-dependent serotonin transporter antagonistHumans U5-hydroxytryptamine receptor 6 antagonistHumans - Absorption
Preclinical pharmacokinetic studies have shown a dose-dependent increase in plasma levels with a tmax between 2-4 hours and Cmax from 6.9-19.6 ng/ml when administered in a dose of 25-100 mg of zotepine. The maximum concentration peaks and slow declines thereafter.4 When administered orally in preclinical studies, zotepine was proven to be absorbed rapidly and almost completely from the gastrointestinal tract.The unchanged drug and metabolites are rapidly distributed to the tissues.5
- Volume of distribution
The apparent volume of distribution of zotepine is 109 L/kg.6
- Protein binding
Plasma protein binding of zotepine and its major active metabolite norzotepine account for 97% of the administered dose.13
- Metabolism
Zotepine is well metabolized in the body, it actually undergoes extensive first-pass metabolism to the metabolite norzotepine and several inactive metabolites. The main enzymes involved in zotepine metabolism are CYP1A2 and CYP3A4.13 Some of the main metabolic pathways include N-demethylation and oxygenation of N or S atoms, hydroxylation of the aromatic ring and consecutive conjugation.5
Hover over products below to view reaction partners
- Route of elimination
Only small amounts of the unchanged zotepine are excreted in the urine and fecal excretion through the bile is the main route of elimination of both the unchanged drug and its metabolites.5
- Half-life
The half-life of zotepine is reported to be of 21 hours.6
- Clearance
The apparent oral clearance of zotepine is 4.6 mg/h.kg.6
- Adverse Effects
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The use of zotepine has been vastly related to ongoing extrapyramidal side effects and it has been reported to be poorly tolerated by the patients.1,2
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Zotepine is combined with 1,2-Benzodiazepine. Abametapir The serum concentration of Zotepine can be increased when it is combined with Abametapir. Abatacept The metabolism of Zotepine can be increased when combined with Abatacept. Abiraterone The serum concentration of Zotepine can be increased when it is combined with Abiraterone. Acenocoumarol The metabolism of Zotepine can be decreased when combined with Acenocoumarol. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Losizopilon / Zoleptil
Categories
- ATC Codes
- N05AX11 — Zotepine
- Drug Categories
- Antidepressive Agents
- Antipsychotic Agents
- Antipsychotic Agents (Second Generation [Atypical])
- Central Nervous System Agents
- Central Nervous System Depressants
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Dopamine Antagonists
- Dopamine D2 Receptor Antagonists
- Heterocyclic Compounds, Fused-Ring
- Nervous System
- Neurotoxic agents
- Psycholeptics
- Psychotropic Drugs
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- Serotonin 5-HT2 Receptor Antagonists
- Serotonin 5-HT2A Receptor Antagonists
- Serotonin Agents
- Serotonin Receptor Antagonists
- Sulfur Compounds
- Thiepins
- Tranquilizing Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as dibenzothiepins. These are compounds containing a dibenzothiepin moiety, which consists of two benzene connected by a thiepine ring.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Benzothiepins
- Sub Class
- Dibenzothiepins
- Direct Parent
- Dibenzothiepins
- Alternative Parents
- Diarylthioethers / Benzenoids / Aryl chlorides / Trialkylamines / Organopnictogen compounds / Organooxygen compounds / Organochlorides / Hydrocarbon derivatives
- Substituents
- Amine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Aryl thioether / Benzenoid / Diarylthioether / Dibenzothiepin / Hydrocarbon derivative / Organic nitrogen compound
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- tertiary amino compound, dibenzothiepine (CHEBI:32316)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- U29O83JAZW
- CAS number
- 26615-21-4
- InChI Key
- HDOZVRUNCMBHFH-UHFFFAOYSA-N
- InChI
- 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
- IUPAC Name
- [2-({6-chloro-2-thiatricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,9,11,13-heptaen-9-yl}oxy)ethyl]dimethylamine
- SMILES
- CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12
References
- General References
- Satoh H, Shimomura K, Mori J: Effect of zotepine on afterdischarge induced by electrical stimulation of amygdaloid nucleus in rats. Jpn J Pharmacol. 1982 Apr;32(2):381-3. [Article]
- Bishnoi RJ, Jhanwar VG: Tolerability of zotepine in Indian patients: Preliminary experience. Ind Psychiatry J. 2010 Jul;19(2):130-1. doi: 10.4103/0972-6748.90345. [Article]
- Saletu B, Grunberger J, Linzmayer L, Anderer P: Comparative placebo-controlled pharmacodynamic studies with zotepine and clozapine utilizing pharmaco-EEG and psychometry. Pharmacopsychiatry. 1987 Feb;20(1 Spec No):12-27. doi: 10.1055/s-2007-1017125. [Article]
- Saletu B, Grunberger J, Anderer P, Chwatal K: [Relation between blood levels and average quantitative EEG and psychometrically assessed pharmacodynamic changes following zotepine]. Fortschr Neurol Psychiatr. 1991 Sep;59 Suppl 1:45-55. doi: 10.1055/s-2007-1000735. [Article]
- Noda K, Suzuki A, Okui M, Noguchi H, Nishiura M, Nishiura N: Pharmacokinetics and metabolism of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]thiepine (zotepine) in rat, mouse, dog and man. Arzneimittelforschung. 1979;29(10):1595-600. [Article]
- Tanaka O, Kondo T, Otani K, Yasui N, Tokinaga N, Kaneko S: Single oral dose kinetics of zotepine and its relationship to prolactin response and side effects. Ther Drug Monit. 1998 Feb;20(1):117-9. [Article]
- Wright P. and O'Neill M. (2012). Core psychiatry (3rd ed.). Elsevier.
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
- FDA Submission [Link]
- FDA antipsychotics [Link]
- EMA reports [Link]
- NIMH [Link]
- Zotepine monograph [Link]
- External Links
- PDB Entries
- 6a94
- MSDS
- Download (52.4 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Terminated Treatment Delirium 1 4 Terminated Treatment Schizophrenia 1 Not Available Completed Not Available Bipolar Disorder (BD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, coated Oral 50 mg Tablet, film coated Oral 25 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 90ºC 'MSDS' boiling point (°C) 478.4ºC 'MSDS' water solubility Poorly soluble Patent US6239165 logP 4.25 'MSDS' - Predicted Properties
Property Value Source Water Solubility 0.000777 mg/mL ALOGPS logP 4.74 ALOGPS logP 4.51 Chemaxon logS -5.6 ALOGPS pKa (Strongest Basic) 8.92 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 12.47 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 97.61 m3·mol-1 Chemaxon Polarizability 36.21 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-9000000000-7a5abea6a8b8bb055491 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4i-0094000000-7d13f2545c6f7e7b1ef8 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-9002000000-8381383fe7eee311ebe9 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4i-0091000000-912a1326874638777318 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-9010000000-39c766fc0caa99a6f330 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4i-0090000000-48c19788721254a01e03 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 169.81741 predictedDeepCCS 1.0 (2019) [M+H]+ 172.1754 predictedDeepCCS 1.0 (2019) [M+Na]+ 178.26855 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- G-protein coupled amine receptor activity
- Specific Function
- Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Components:
References
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Potassium channel regulator activity
- Specific Function
- Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
- Gene Name
- DRD2
- Uniprot ID
- P14416
- Uniprot Name
- D(2) dopamine receptor
- Molecular Weight
- 50618.91 Da
References
- Suzuki H, Gen K, Inoue Y: Comparison of the anti-dopamine D(2) and anti-serotonin 5-HT(2A) activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof. J Psychopharmacol. 2013 Apr;27(4):396-400. doi: 10.1177/0269881113478281. Epub 2013 Feb 20. [Article]
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Virus receptor activity
- Specific Function
- G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
- Gene Name
- HTR2A
- Uniprot ID
- P28223
- Uniprot Name
- 5-hydroxytryptamine receptor 2A
- Molecular Weight
- 52602.58 Da
References
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Serotonin receptor activity
- Specific Function
- This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
- Gene Name
- HTR7
- Uniprot ID
- P34969
- Uniprot Name
- 5-hydroxytryptamine receptor 7
- Molecular Weight
- 53554.43 Da
References
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Norepinephrine:sodium symporter activity
- Specific Function
- Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
- Gene Name
- SLC6A2
- Uniprot ID
- P23975
- Uniprot Name
- Sodium-dependent noradrenaline transporter
- Molecular Weight
- 69331.42 Da
References
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Serotonin:sodium symporter activity
- Specific Function
- Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
- Gene Name
- SLC6A4
- Uniprot ID
- P31645
- Uniprot Name
- Sodium-dependent serotonin transporter
- Molecular Weight
- 70324.165 Da
References
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- General Function
- Serotonin receptor activity
- Specific Function
- This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
- Gene Name
- HTR6
- Uniprot ID
- P50406
- Uniprot Name
- 5-hydroxytryptamine receptor 6
- Molecular Weight
- 46953.625 Da
References
- Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Zotepine monograph [Link]
Drug created at October 22, 2015 20:22 / Updated at February 21, 2021 18:52