Chlorprothixene

Identification

Summary

Chlorprothixene is a thioxanthene antipsychotic.

Generic Name
Chlorprothixene
DrugBank Accession Number
DB01239
Background

Chlorprothixene is a typical antipsychotic drug of the thioxanthene (tricyclic) class. Chlorprothixene exerts strong blocking effects by blocking the 5-HT2 D1, D2, D3, histamine H1, muscarinic and alpha1 adrenergic receptors.

Type
Small Molecule
Groups
Approved, Experimental, Investigational, Withdrawn
Structure
Weight
Average: 315.86
Monoisotopic: 315.0848485
Chemical Formula
C18H18ClNS
Synonyms
  • Alpha-Chlorprothixene
  • Chlorprothixen
  • Chlorprothixene
  • Chlorprothixine
  • Chlorprotixen
  • Chlorprotixene
  • Chlorprotixine
  • Chlothixen

Pharmacology

Indication

For treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occuring as part of bipolar disorders.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofPsychosis••••••••••••••••••
Treatment ofSchizophrenia••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Chlorprothixene is a typical antipsychotic drug of the thioxanthine class. It has a low antipsychotic potency (half to 2/3 of chlorpromazine). Chlorprothixene has not thoroughly demonstrated an antidepressant or analgesic effect but it has demonstrated antiemetic effects. It is used in the treatment of nervous, mental, and emotional conditions. Improvement in such conditions is thought to result from the effect of the medicine on nerve pathways in specific areas of the brain. Chlorprothixene has a similar side effect profile to chlorpromazine, though allergic side effects and liver damage are less frequent.

Mechanism of action

Chlorprothixene blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

TargetActionsOrganism
ADopamine D2 receptor
antagonist
Humans
ADopamine D1 receptor
antagonist
Humans
ADopamine D3 receptor
antagonist
Humans
A5-hydroxytryptamine receptor 2A
antagonist
Humans
AHistamine H1 receptor
antagonist
Humans
ASerotonin Receptors
inhibitor
Humans
NMuscarinic acetylcholine receptor M1
antagonist
Humans
NMuscarinic acetylcholine receptor M2
antagonist
Humans
NMuscarinic acetylcholine receptor M3
antagonist
Humans
NMuscarinic acetylcholine receptor M4
antagonist
Humans
NMuscarinic acetylcholine receptor M5
antagonist
Humans
Absorption

Incomplete bioavailability.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic

Route of elimination

Not Available

Half-life

8 to 12 hours

Clearance

Not Available

Adverse Effects
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Toxicity

Symptoms of overdose include difficulty in breathing (severe), dizziness (severe), drowsiness (severe), muscle trembling, jerking, stiffness, or uncontrolled movements (severe), small pupils, unusual excitement, and unusual tiredness or weakness (severe).

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Chlorprothixene is combined with 1,2-Benzodiazepine.
AcenocoumarolThe risk or severity of adverse effects can be increased when Chlorprothixene is combined with Acenocoumarol.
AcetazolamideThe risk or severity of CNS depression can be increased when Acetazolamide is combined with Chlorprothixene.
AcetophenazineThe risk or severity of CNS depression can be increased when Acetophenazine is combined with Chlorprothixene.
AclidiniumThe risk or severity of adverse effects can be increased when Chlorprothixene is combined with Aclidinium.
Food Interactions
  • Avoid alcohol.
  • Take with food. Food reduces irritation.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Chlorprothixene hydrochloride268KCR965N6469-93-8YWKRLOSRDGPEJR-KIUKIJHYSA-N
International/Other Brands
Clothixen (Yoshitomi) / Cloxan (Orion) / Taractan (Roche)

Categories

ATC Codes
N05AF03 — Chlorprothixene
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
9S7OD60EWP
CAS number
113-59-7
InChI Key
WSPOMRSOLSGNFJ-AUWJEWJLSA-N
InChI
InChI=1S/C18H18ClNS/c1-20(2)11-5-7-14-15-6-3-4-8-17(15)21-18-10-9-13(19)12-16(14)18/h3-4,6-10,12H,5,11H2,1-2H3/b14-7-
IUPAC Name
{3-[(9Z)-2-chloro-9H-thioxanthen-9-ylidene]propyl}dimethylamine
SMILES
CN(C)CC\C=C1\C2=CC=CC=C2SC2=CC=C(Cl)C=C12

References

Synthesis Reference

Sprague, J.M. and Engelhardt, E.L.; US. Patent 2,951,082; August 30, 1960; assigned to Merck & Co., Inc. Schlapfer, R. and Spiegelberg, H.; US. Patent 3,115,502; December 24,1963; assigned to Hoffmann-LaRoche Inc.

US3046283
General References
Not Available
KEGG Drug
D00790
KEGG Compound
C07953
PubChem Compound
667466
PubChem Substance
46508957
ChemSpider
580849
BindingDB
50240514
RxNav
2406
ChEBI
50931
ChEMBL
CHEMBL908
ZINC
ZINC000000001137
Therapeutic Targets Database
DAP000833
PharmGKB
PA164781400
Wikipedia
Chlorprothixene
MSDS
Download (63.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3TerminatedTreatmentAnxiety Disorders / Dementia / Depression / Psychosomatic Disorders / Schizophrenia1
Not AvailableCompletedNot AvailableBipolar Disorder (BD) / Psychosis / Schizoaffective Disorders / Schizophrenia / Type 2 Diabetes Mellitus1
Not AvailableRecruitingNot AvailableObesity, Morbid1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral15 mg/1
Tablet, film coatedOral50 mg/1
Tablet, film coatedOral90 mg/1
Tablet, film coatedOral15 MG
Tablet, film coatedOral50 MG
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)153-154Sprague, J.M. and Engelhardt, E.L.; US. Patent 2,951,082; August 30, 1960; assigned to Merck & Co., Inc. Schlapfer, R. and Spiegelberg, H.; US. Patent 3,115,502; December 24,1963; assigned to Hoffmann-LaRoche Inc.
water solubility0.295 mg/LNot Available
logP5.18HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.000366 mg/mLALOGPS
logP5.42ALOGPS
logP5.07Chemaxon
logS-5.9ALOGPS
pKa (Strongest Basic)9.76Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count1Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area3.24 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity104.66 m3·mol-1Chemaxon
Polarizability35.77 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9899
Blood Brain Barrier+0.95
Caco-2 permeable+0.7404
P-glycoprotein substrateSubstrate0.8042
P-glycoprotein inhibitor IInhibitor0.8407
P-glycoprotein inhibitor IIInhibitor0.8884
Renal organic cation transporterInhibitor0.72
CYP450 2C9 substrateNon-substrate0.7199
CYP450 2D6 substrateSubstrate0.6845
CYP450 3A4 substrateSubstrate0.7096
CYP450 1A2 substrateInhibitor0.9106
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8931
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8308
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.768
Ames testNon AMES toxic0.7084
CarcinogenicityNon-carcinogens0.8714
BiodegradationNot ready biodegradable0.9838
Rat acute toxicity3.1665 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8117
hERG inhibition (predictor II)Inhibitor0.7373
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.22 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-01b9-0059000000-42b939b1ca50abc0dc7f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0009000000-93ef2c8704ae801d71a5
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-2094000000-bbec5a732c2dec06b607
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-2069000000-66607713632d4be4377e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-05g0-0090000000-5d056817edc427a9901e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9010000000-1317deaef4a4eac32efa
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details
1. Dopamine D2 receptor
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
  1. Froimowitz M, Cody V: Biologically active conformers of phenothiazines and thioxanthenes. Further evidence for a ligand model of dopamine D2 receptor antagonists. J Med Chem. 1993 Jul 23;36(15):2219-27. [Article]
  2. Fux M, Belmaker RH: A controlled comparative study of chlorprothixene vs. haloperidol in chronic schizophrenia. Isr J Psychiatry Relat Sci. 1991;28(1):37-40. [Article]
  3. von Coburg Y, Kottke T, Weizel L, Ligneau X, Stark H: Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics. Bioorg Med Chem Lett. 2009 Jan 15;19(2):538-42. doi: 10.1016/j.bmcl.2008.09.012. Epub 2008 Sep 7. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Details
2. Dopamine D1 receptor
Kind
Protein
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.
Gene Name
DRD1
Uniprot ID
P21728
Uniprot Name
D(1A) dopamine receptor
Molecular Weight
49292.765 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Fux M, Belmaker RH: A controlled comparative study of chlorprothixene vs. haloperidol in chronic schizophrenia. Isr J Psychiatry Relat Sci. 1991;28(1):37-40. [Article]
Details
3. Dopamine D3 receptor
Kind
Protein
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 inhibit adenylyl cyclase. Promotes cell proliferation.
Gene Name
DRD3
Uniprot ID
P35462
Uniprot Name
D(3) dopamine receptor
Molecular Weight
44224.335 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Fux M, Belmaker RH: A controlled comparative study of chlorprothixene vs. haloperidol in chronic schizophrenia. Isr J Psychiatry Relat Sci. 1991;28(1):37-40. [Article]
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
  1. Antkiewicz-Michaluk L: The influence of chronic treatment with antidepressant neuroleptics on the central serotonin system. Pol J Pharmacol Pharm. 1986 Jul-Aug;38(4):359-70. [Article]
  2. Wander TJ, Nelson A, Okazaki H, Richelson E: Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro. Eur J Pharmacol. 1987 Nov 10;143(2):279-82. [Article]
Details
5. Histamine H1 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Curator comments
Some in vitro studies provide evidence of this target relationship, however, further research is warranted.
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
References
  1. Vasudevan SR, Moore JB, Schymura Y, Churchill GC: Shape-based reprofiling of FDA-approved drugs for the H(1) histamine receptor. J Med Chem. 2012 Aug 23;55(16):7054-60. doi: 10.1021/jm300671m. Epub 2012 Aug 6. [Article]
  2. Ding P, Yan X, Liu Z, Du J, Du Y, Lu Y, Wu D, Xu Y, Zhou H, Gu Q, Xu J: PTS: a pharmaceutical target seeker. Database (Oxford). 2017 Jan 1;2017. pii: 4781737. doi: 10.1093/database/bax095. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Not all literature specifies the specificity of this drug for the serotonin receptor subtypes.
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...

Components:
References
  1. Drummond AH, Whigham KA, Prentice CR: Effects of chlorprothixene isomers on platelet 5-hydroxytryptamine receptors: evidence for different 5-hydroxytryptamine conformations at uptake and stimulatory sites. Eur J Pharmacol. 1976 Jun;37(2):385-8. doi: 10.1016/0014-2999(76)90047-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
G-protein coupled acetylcholine receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM4
Uniprot ID
P08173
Uniprot Name
Muscarinic acetylcholine receptor M4
Molecular Weight
53048.65 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM5
Uniprot ID
P08912
Uniprot Name
Muscarinic acetylcholine receptor M5
Molecular Weight
60073.205 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. [Article]

Drug created at June 13, 2005 13:24 / Updated at June 09, 2021 08:40