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Identification
NameChlorprothixene
Accession NumberDB01239  (APRD00718)
Typesmall molecule
Groupsapproved, withdrawn
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
Alpha-ChlorprothixeneNot AvailableNot Available
ChlorprothixenNot AvailableNot Available
ChlorprothixineNot AvailableNot Available
ChlorprotixenNot AvailableNot Available
ChlorprotixeneNot AvailableNot Available
ChlorprotixineNot AvailableNot Available
ChlothixenNot AvailableNot Available
SID11110647Not AvailableNot Available
SID144203583Not AvailableNot Available
SID4253130Not AvailableNot Available
SID50108484Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ClothixenYoshitomi
CloxanOrion
TaractanRoche
Brand mixturesNot Available
Categories
CAS number113-59-7
WeightAverage: 315.86
Monoisotopic: 315.084847978
Chemical FormulaC18H18ClNS
InChI KeyWSPOMRSOLSGNFJ-VGOFMYFVSA-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-(2-chloro-9H-thioxanthen-9-ylidene)propyl]dimethylamine
SMILES
[H]C(CCN(C)C)=C1C2=CC(Cl)=CC=C2SC2=C1C=CC=C2
Mass Specshow(8.22 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzopyrans
SubclassThioxanthenes
Direct parentThioxanthenes
Alternative parentsChlorobenzenes; Aryl Chlorides; Tertiary Amines; Polyamines; Thioethers; Organochlorides
Substituentschlorobenzene; aryl halide; aryl chloride; benzene; tertiary amine; polyamine; thioether; organochloride; organohalogen; amine; organonitrogen compound
Classification descriptionThis compound belongs to the thioxanthenes. These are organic polycyclic compounds containing a thioxanthene moiety, which is an aromatic tricycle derived from xanthene by replacing the oxygen atom with a sulfur atom.
Pharmacology
IndicationFor treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occuring as part of bipolar disorders.
PharmacodynamicsChlorprothixene is a typical antipsychotic drug of the thioxanthine class. It has a low antipsychotic potency (half to 2/3 of chlorpromazine). An intrinsic antidepressant effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine analgesic effects. An antiemetic effect, as with most antipsychotics, exists. 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 strong sedative activity with a high incidence of anticholinergic side-effects. Chlorprothixene is structurally related to chlorpromazine, with which it shares in principal all side effects. Allergic side-effects and liver damage seem to appear with an appreciable lower frequency.
Mechanism of actionChlorprothixene 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.
AbsorptionIncomplete bioavailability.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic

Route of eliminationNot Available
Half life8 to 12 hours
ClearanceNot Available
ToxicitySymptoms 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).
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9899
Blood Brain Barrier + 0.95
Caco-2 permeable + 0.7404
P-glycoprotein substrate Substrate 0.8042
P-glycoprotein inhibitor I Inhibitor 0.8407
P-glycoprotein inhibitor II Inhibitor 0.8884
Renal organic cation transporter Inhibitor 0.72
CYP450 2C9 substrate Non-substrate 0.7199
CYP450 2D6 substrate Substrate 0.6845
CYP450 3A4 substrate Substrate 0.7096
CYP450 1A2 substrate Inhibitor 0.9106
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8931
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8308
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.768
Ames test Non AMES toxic 0.7084
Carcinogenicity Non-carcinogens 0.8714
Biodegradation Not ready biodegradable 0.9838
Rat acute toxicity 3.1665 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8117
hERG inhibition (predictor II) Inhibitor 0.7373
Pharmacoeconomics
Manufacturers
  • Hoffmann la roche inc
PackagersNot Available
Dosage forms
FormRouteStrength
ConcentrateOral
SolutionIntramuscular
SyrupOral
TabletOral
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point153-154Sprague, 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 solubility3.66e-04 g/lALOGPS
logP5.42ALOGPS
logP5.07ChemAxon
logS-5.9ALOGPS
pKa (strongest basic)9.76ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count1ChemAxon
hydrogen donor count0ChemAxon
polar surface area3.24ChemAxon
rotatable bond count3ChemAxon
refractivity104.66ChemAxon
polarizability35.85ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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 ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00790
KEGG CompoundC07953
ChEBI3651
ChEMBLCHEMBL908
Therapeutic Targets DatabaseDAP000833
PharmGKBPA164781400
WikipediaChlorprothixene
ATC CodesN05AF03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(63.3 KB)
Interactions
Drug Interactions
Drug
DonepezilPossible antagonism of action
GalantaminePossible antagonism of action
GuanethidineChlorprothixene may decrease the effect of guanethidine.
RivastigminePossible antagonism of action
Food Interactions
  • Avoid alcohol.
  • Take with food to reduce irritation.

Targets

1. D(2) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
D(2) dopamine receptor P14416 Details

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. Pubmed
  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. Pubmed
  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. Epub 2008 Sep 7. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. D(1A) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
D(1A) dopamine receptor P21728 Details

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. Pubmed
  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. Pubmed
  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. Pubmed

3. D(3) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
D(3) dopamine receptor P35462 Details

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. Pubmed
  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. Pubmed
  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. Pubmed

4. 5-hydroxytryptamine receptor 2A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2A P28223 Details

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. Pubmed
  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. Pubmed

5. 5-hydroxytryptamine receptor 2B

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2B P41595 Details

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. Pubmed
  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. Pubmed

6. 5-hydroxytryptamine receptor 2C

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2C P28335 Details

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. Pubmed
  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. Pubmed

7. Histamine H1 receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Histamine H1 receptor P35367 Details

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. Pubmed
  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. Pubmed

8. Muscarinic acetylcholine receptor M1

Kind: protein

Organism: Human

Pharmacological action: no

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M1 P11229 Details

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. Pubmed

9. Muscarinic acetylcholine receptor M2

Kind: protein

Organism: Human

Pharmacological action: no

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M2 P08172 Details

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. Pubmed

10. Muscarinic acetylcholine receptor M3

Kind: protein

Organism: Human

Pharmacological action: no

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M3 P20309 Details

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. Pubmed

11. Muscarinic acetylcholine receptor M4

Kind: protein

Organism: Human

Pharmacological action: no

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M4 P08173 Details

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. Pubmed

12. Muscarinic acetylcholine receptor M5

Kind: protein

Organism: Human

Pharmacological action: no

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M5 P08912 Details

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. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

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. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 04, 2014 11:55