Identification

Name
Zotepine
Accession Number
DB09225
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

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]

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Losizopilon / Zoleptil
Categories
UNII
U29O83JAZW
CAS number
26615-21-4
Weight
Average: 331.86
Monoisotopic: 331.0797631
Chemical Formula
C18H18ClNOS
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

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]

Pharmacodynamics

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]

TargetActionsOrganism
AD(1) dopamine receptor
antagonist
Human
AD(2) dopamine receptor
antagonist
Human
A5-hydroxytryptamine receptor 2A
antagonist
Human
U5-hydroxytryptamine receptor 6
antagonist
Human
A5-hydroxytryptamine receptor 7
antagonist
Human
ASodium-dependent noradrenaline transporter
antagonist
Human
ASodium-dependent serotonin transporter
antagonist
Human
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]

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]

Toxicity

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]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamineZotepine may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineZotepine may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineZotepine may decrease the stimulatory activities of 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineZotepine may decrease the stimulatory activities of 4-Bromo-2,5-dimethoxyamphetamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Zotepine.
AbirateroneThe serum concentration of Zotepine can be increased when it is combined with Abiraterone.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Zotepine.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Zotepine.
Acetyl sulfisoxazoleThe metabolism of Zotepine can be decreased when combined with Acetyl sulfisoxazole.
AdipiplonThe risk or severity of adverse effects can be increased when Adipiplon is combined with Zotepine.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:6124648]
  2. 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. [PubMed:22174537]
  3. 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. [PubMed:2883677]
  4. 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. [PubMed:1683340]
  5. 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. [PubMed:42414]
  6. 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. [PubMed:9485566]
  7. Wright P. and O'Neill M. (2012). Core psychiatry (3rd ed.). Elsevier.
  8. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
  9. FDA Submission [Link]
  10. FDA antipsychotics [Link]
  11. EMA reports [Link]
  12. NIMH [Link]
  13. Zotepine monograph [Link]
External Links
KEGG Drug
D01321
PubChem Compound
5736
PubChem Substance
310265131
ChemSpider
5534
BindingDB
35255
ChEBI
32316
ChEMBL
CHEMBL285802
Wikipedia
Zotepine
ATC Codes
N05AX11 — Zotepine
MSDS
Download (52.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4TerminatedTreatmentSchizophrenic Disorders1
Not AvailableCompletedNot AvailableBipolar Disorder (BD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)90ºC'MSDS'
boiling point (°C)478.4ºC'MSDS'
water solubilityPoorly soluble Patent US6239165
logP4.25'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.000777 mg/mLALOGPS
logP4.74ALOGPS
logP4.51ChemAxon
logS-5.6ALOGPS
pKa (Strongest Basic)8.92ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity97.61 m3·mol-1ChemAxon
Polarizability36.21 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Dibenzothiepin / Diarylthioether / Aryl thioether / Aryl chloride / Aryl halide / Benzenoid / Tertiary amine / Tertiary aliphatic amine / Thioether / Organic oxygen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, dibenzothiepine (CHEBI:32316)

Targets

Kind
Protein group
Organism
Human
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
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Human
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
  1. 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. [PubMed:23427194]
  2. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Human
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
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Human
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
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Human
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
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Human
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
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Human
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
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.

Enzymes

Kind
Protein
Organism
Human
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
  1. Zotepine monograph [Link]
Kind
Protein
Organism
Human
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
  1. Zotepine monograph [Link]

Drug created on October 22, 2015 14:22 / Updated on August 02, 2018 06:15