Chlorprothixene (original) (raw)

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Description

A medication used to treat psychiatric conditions like schizophrenia.

Description

A medication used to treat psychiatric conditions like schizophrenia.

DrugBank ID

DB01239

Type

Small Molecule

US Approved

NO

Other Approved

YES

Mechanism of Action

• D(2) dopamine receptor
  Antagonist
• D(1A) dopamine receptor
  Antagonist
• D(3) dopamine receptor
  Antagonist
• + 3 more targets

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Approved, Experimental, Investigational, Withdrawn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

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

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.

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

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Food Interactions

• Avoid alcohol.
• Take with food. Food reduces irritation.

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Product Ingredients

International/Other Brands

Clothixen (Yoshitomi) / Cloxan (Orion) / Taractan (Roche)

ATC Codes

N05AF03 — Chlorprothixene

• N05AF — Thioxanthene derivatives
• N05A — ANTIPSYCHOTICS
• N05 — PSYCHOLEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Agents producing tachycardia
• Anticholinergic Agents
• Antidepressive Agents
• Antipsychotic Agents
• Antipsychotic Agents (First Generation [Typical])
• Central Nervous System Agents
• Central Nervous System Depressants
• Dopamine Agents
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Heterocyclic Compounds, Fused-Ring
• Histamine Antagonists
• Histamine H1 Antagonists
• Muscarinic Antagonists
• Nervous System
• Neurotoxic agents
• Neurotransmitter Agents
• P-glycoprotein inhibitors
• Potential QTc-Prolonging Agents
• Psycholeptics
• Psychotropic Drugs
• QTc Prolonging Agents
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin 5-HT2A Receptor Antagonists
• Serotonin Agents
• Serotonin Receptor Antagonists
• Sulfur Compounds
• Thioxanthene Derivatives
• Thioxanthenes
• Tranquilizing Agents
• Xanthenes

Classification

Not classified

Affected organisms

• Humans and other mammals

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

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

External Links

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

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

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Preview package

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Prices

Not Available

Patents

Not Available

State

Solid

Experimental Properties

Predicted Properties

Predicted ADMET Features

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Mass Spec (NIST)

Download (8.22 KB)

Spectra

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase (PubMed:21645528). Positively regulates postnatal regression of retinal hyaloid vessels via suppression of VEGFR2/KDR activity, downstream of OPN5 (By similarity)

Specific Function

dopamine binding

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]
5. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase

Specific Function

arrestin family protein binding

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]

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation

Specific Function

dopamine neurotransmitter receptor activity, coupled via Gi/Go

Gene Name

DRD3

Uniprot ID

P35462

Uniprot Name

D(3) dopamine receptor

Molecular Weight

44194.315 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

G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895, PubMed:21645528, PubMed:22300836, PubMed:35084960, PubMed:38552625). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538, PubMed:35084960). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:28129538, PubMed:35084960). HTR2A is coupled to G(q)/G(11) G alpha proteins and activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers that modulate the activity of phosphatidylinositol 3-kinase and promote the release of Ca(2+) ions from intracellular stores, respectively (PubMed:18703043, PubMed:28129538, PubMed:35084960). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538, PubMed:35084960). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction (By similarity)

Specific Function

1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding

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]

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

Some in vitro studies provide evidence of this target relationship, however, further research is warranted.

General Function

G-protein-coupled receptor for histamine, a biogenic amine that functions as an immune modulator and a neurotransmitter (PubMed:33828102, PubMed:8280179). Through the H1 receptor, histamine mediates the contraction of smooth muscles and increases capillary permeability due to contraction of terminal venules. Also mediates neurotransmission in the central nervous system and thereby regulates circadian rhythms, emotional and locomotor activities as well as cognitive functions (By similarity)

Specific Function

G protein-coupled serotonin receptor activity

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

Not all literature specifies the specificity of this drug for the serotonin receptor subtypes.

General Function

G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:22957663, PubMed:3138543, PubMed:33762731, PubMed:37935376, PubMed:37935377, PubMed:8138923, PubMed:8393041). Also functions as a receptor for various drugs and psychoactive substances (PubMed:22957663, PubMed:3138543, PubMed:33762731, PubMed:38552625, PubMed:8138923, PubMed:8393041). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:22957663, PubMed:3138543, PubMed:33762731, PubMed:8138923, PubMed:8393041). HTR1A is coupled to G(i)/G(o) G alpha proteins and mediates inhibitory neurotransmission: signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores (PubMed:33762731, PubMed:35610220). Beta-arrestin family members regulate signaling by mediating both receptor desensitization and resensitization processes (PubMed:18476671, PubMed:20363322, PubMed:20945968). Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism (PubMed:18476671, PubMed:20363322, PubMed:20945968). Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior (PubMed:18476671, PubMed:20363322, PubMed:20945968). Plays a role in the response to anxiogenic stimuli (PubMed:18476671, PubMed:20363322, PubMed:20945968)

Specific Function

G protein-coupled serotonin receptor activity

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

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Specific Function

G protein-coupled acetylcholine receptor activity

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

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol

Specific Function

arrestin family protein binding

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

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Specific Function

acetylcholine binding

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

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase

Specific Function

G protein-coupled acetylcholine receptor activity

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

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Specific Function

G protein-coupled acetylcholine receptor activity

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

Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)

Specific Function

ABC-type xenobiotic transporter activity

Gene Name

ABCB1

Uniprot ID

P08183

Uniprot Name

ATP-dependent translocase ABCB1

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