HALOPERIDOL

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H23ClFNO2
Molecular Weight	375.864
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC1(CCN(CCCC(=O)C2=CC=C(F)C=C2)CC1)C3=CC=C(Cl)C=C3

InChI

InChIKey=LNEPOXFFQSENCJ-UHFFFAOYSA-N

InChI=1S/C21H23ClFNO2/c22-18-7-5-17(6-8-18)21(26)11-14-24(15-12-21)13-1-2-20(25)16-3-9-19(23)10-4-16/h3-10,26H,1-2,11-15H2

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00502
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/015923s079lbl.pdf

Haloperidol is a phenyl-piperidinyl-butyrophenone that is used primarily to treat schizophrenia and other psychoses. It is also used in schizoaffective disorder, delusional disorders, ballism, and Tourette syndrome (a drug of choice) and occasionally as adjunctive therapy in mental retardation and the chorea of Huntington disease. It is a potent antiemetic and is used in the treatment of intractable hiccups. Haloperidol also exerts sedative and antiemetic activity. Haloperidol principal pharmacological effects are similar to those of piperazine-derivative phenothiazines. The drug has action at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Haloperidol has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. The precise mechanism whereby the therapeutic effects of haloperidol are produced is not known, but the drug appears to depress the CNS at the subcortical level of the brain, midbrain, and brain stem reticular formation. Haloperidol seems to inhibit the ascending reticular activating system of the brain stem (possibly through the caudate nucleus), thereby interrupting the impulse between the diencephalon and the cortex. The drug may antagonize the actions of glutamic acid within the extrapyramidal system, and inhibitions of catecholamine receptors may also contribute to haloperidol's mechanism of action. Haloperidol may also inhibit the reuptake of various neurotransmitters in the midbrain, and appears to have a strong central antidopaminergic and weak central anticholinergic activity. The drug produces catalepsy and inhibits spontaneous motor activity and conditioned avoidance behaviours in animals. The exact mechanism of antiemetic action of haloperidol has also not been fully determined, but the drug has been shown to directly affect the chemoreceptor trigger zone (CTZ) through the blocking of dopamine receptors in the CTZ. Haloperidol is marketed under the trade name Haldol among others.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Dopamine D4 receptor 76 Target ID: CHEMBL219 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14611858	Inverse Agonist 85	17.0 nM [EC50]
Dopamine D2 receptor 311 Target ID: CHEMBL217 Sources: http://www.drugbank.ca/drugs/DB00502	Antagonist 2849
Serotonin 2a (5-HT2a) receptor 237 Target ID: CHEMBL224 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7520908	Antagonist 2849	53.0 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 305 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/015923s079lbl.pdf	Primary		Approved 8583	HALDOL Approved Use HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. Launch Date 1986
Tourette's syndrome 20 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/015923s079lbl.pdf	Primary		Approved 8583	HALDOL Approved Use HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia. HALDOL is indicated for the control of tics and vocal utterances of Tourette’s Disorder. Launch Date 1986

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252	substrate 1193 inhibitor 2438	substrate 1388 activator 25 inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2J2 33 P-gp 1741 OCT1 620 BCRP 910 MRP2 499 MDR3 8 Kv4.3 16 CYP1A2 2153 CYP2A6 879 CYP2C8 1057 CYP2C19 2057 CYP2E1 1060 BSEP 550 MRP3 246 MRP4 290 OATP1B1 1079 OATP1B3 961	CYP1A2 1197 CYP1A1 389 CYP2C8 810 CYP2C19 1119 CYP3A5 446 UGT 219 UGT1A1 479 UGT1A3 470 UGT1A4 399 UGT1A6 343 UGT1A9 423 UGT2B7 456 UGT2B15 236 P-gp 2052 OCT1 393 MATE1 182

Drug as perpetrator

Target	Modality	Activity
CYP2D6 2546	inhibitor 4027 Sources: https://link.springer.com/article/10.1007/s40262-016-0407-2/tables/3 \| https://pubmed.ncbi.nlm.nih.gov/10460810/	moderate [Ki 7.2 uM]
CYP2A6 911	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw1MjgyIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDU0In19	no [IC50 >10 uM]
CYP2E1 1146	inhibitor 4027 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw1MjgxIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDU0In19	no [IC50 >10 uM]
MRP2 625	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19421845/, https://pubmed.ncbi.nlm.nih.gov/23956101/, https://pubmed.ncbi.nlm.nih.gov/18457386/	no [IC50 >133 uM]
MRP3 326	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23956101/	no [IC50 >133 uM]
MRP4 345	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23956101/	no [IC50 >133 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336800/	no [IC50 >30 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/9431831/, https://pubmed.ncbi.nlm.nih.gov/23033255/	no [IC50 >50 uM]
BCRP 985	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19421845/	no
CYP2C9 2497	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/9431831/, https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwzMzk3IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDU0In19	yes [Activation 31.6228 uM]
MDR3 9	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/26335978/	yes [IC50 10.7 uM]
OCT1 656	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/18788725/	yes [IC50 141.9 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336800/	yes [IC50 2.87 uM]
BSEP 554	inhibitor 4027 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891329/, https://pubmed.ncbi.nlm.nih.gov/23956101/	yes [IC50 25.3 uM]
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/16810505/	yes [IC50 25.4 uM]
Kv4.3 16	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/24998874/	yes [IC50 3.6 uM]
CYP2J2 36	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23033255/	yes [IC50 4.69 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/9431831/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336800/	yes [IC50 8.2 uM]
CYP2D6 2546	activator 342 Sources: https://pubmed.ncbi.nlm.nih.gov/9681669/, https://bioinformatics.charite.de/transformer/index.php?site=fullinfo&cname=000052868	yes
OATP1B1 1095	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23571415/	yes
OATP1B3 970	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23571415/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/12031686/	likely [Km 33 uM]
UGT 219	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/015923s093s098,018701s071s076lbl.pdf#page=8 Page: (Label) 8, 27	major
UGT2B7 456	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/32294459/	major
CYP2D6 1388	substrate 4014 Sources: https://link.springer.com/article/10.1007/s40262-016-0407-2/tables/3, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/015923s093s098,018701s071s076lbl.pdf#page=9, https://ncit-stage.nci.nih.gov/ncitbrowser/pages/concept_details.jsf?dictionary=NCI_Thesaurus&version=21.02d&code=C537&ns=ncit&type=relationship&key=113214754&b=1&n=0&vse=null Page: (Label) 9, 28	major	yes (co-administration study) Comment: Coadministration of CYP2D6 inhibitors (chlorpromazine, promethazine, quinidine, paroxetine, sertraline, venlafaxine) increased Haloperidol plasma concentrations. Sources: https://link.springer.com/article/10.1007/s40262-016-0407-2/tables/3, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/015923s093s098,018701s071s076lbl.pdf#page=9, https://ncit-stage.nci.nih.gov/ncitbrowser/pages/concept_details.jsf?dictionary=NCI_Thesaurus&version=21.02d&code=C537&ns=ncit&type=relationship&key=113214754&b=1&n=0&vse=null Page: (Label) 9, 28
CYP3A4 1946	substrate 4014 Sources: https://link.springer.com/article/10.1007/s40262-016-0407-2/tables/3, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/015923s093s098,018701s071s076lbl.pdf#page=9, https://ncit-stage.nci.nih.gov/ncitbrowser/pages/concept_details.jsf?dictionary=NCI_Thesaurus&version=21.02d&code=C537&ns=ncit&type=relationship&key=113214754&b=1&n=0&vse=null Page: (Label) 9, 28	major	yes (co-administration study) Comment: Coadministration of Rifampicin (strong CYP3A4 inducer) decreased plasma Haloperidol levels by a mean of 70%. Sources: https://link.springer.com/article/10.1007/s40262-016-0407-2/tables/3, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/015923s093s098,018701s071s076lbl.pdf#page=9, https://ncit-stage.nci.nih.gov/ncitbrowser/pages/concept_details.jsf?dictionary=NCI_Thesaurus&version=21.02d&code=C537&ns=ncit&type=relationship&key=113214754&b=1&n=0&vse=null Page: (Label) 9, 28
CYP1A2 1197	substrate 4014 Sources: https://link.springer.com/article/10.1007/s40262-016-0407-2/tables/3, https://ncit-stage.nci.nih.gov/ncitbrowser/pages/concept_details.jsf?dictionary=NCI_Thesaurus&version=21.02d&code=C537&ns=ncit&type=relationship&key=113214754&b=1&n=0&vse=null	minor
UGT1A4 399	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/32294459/	minor
UGT1A9 423	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/32294459/	minor
UGT1A1 479	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/32294459/	no
UGT1A3 470	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/32294459/	no
UGT1A6 343	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/32294459/	no
UGT2B15 236	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/32294459/	no
CYP1A1 389	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/11717183/	yes
CYP2C19 1119	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/11717183/	yes
CYP2C8 810	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/11717183/	yes
CYP2C9 1193	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/11717183/	yes
CYP3A5 446	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/11717183/	yes
MATE1 182	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/31842924/	yes
OCT1 393	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/31842924/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/18448342/, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/015923s093s098,018701s071s076lbl.pdf#page=9, https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1038/sj.bjp.0705025 Page: (Label) 9, 28

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:5613	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:5613
ChemicalBook	CB32131152	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32131152
ChemicalBook	CB72509133	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB72509133
ChemicalBook	CB7774829	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7774829
eMolecules	538987	https://www.emolecules.com/cgi-bin/more?vid=538987
MolPort	MolPort-000-883-311	https://www.molport.com/shop/molecule-link/MolPort-000-883-311
Selleck Chemicals	Haloperidol(Haldol)	http://www.selleckchem.com/products/Haloperidol(Haldol).html
ZINC	ZINC000000537822	http://zinc15.docking.org/substances/ZINC000000537822

PubMed

Title	Date	PubMed
Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients.	1975	1096218
Atypical tardive dyskinesia.	1975 May	1119614
Drug-induced dystonia.	1975 May	1119613
Catalepsy induced by morphine or haloperidol: effects of apomorphine and anticholinergic drugs.	1976 Aug	10058
Papaverine, drug-induced stereotypy and catalepsy and biogenic amines in the brain of the rat.	1976 Jul	1033561
Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy.	1979 Mar 29	108749
A case of neuroleptic-induced unilateral akathisia with periodic limb movements in the opposite side during sleep.	1999 Apr	10459715
Pentadecapeptide BPC 157 attenuates disturbances induced by neuroleptics: the effect on catalepsy and gastric ulcers in mice and rats.	1999 Aug 20	10499368
Reduced haloperidol does not interfere with the antipsychotic activity of haloperidol in the treatment of acute schizophrenia.	1999 Jul	10468314
Safety of amisulpride (Solian): a review of 11 clinical studies.	1999 Jul	10468313
Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics.	1999 Nov	10669905
Hypotension associated with clozapine after cardiopulmonary bypass.	1999 Oct	10527233
Enhanced striatal dopamine D(2) receptor-induced [35S]GTPgammaS binding after haloperidol treatment.	1999 Oct 8	10528146
Transient syncope and ECG changes associated with the concurrent administration of clozapine and diazepam.	1999 Sep	10520983
Identification of quantitative trait loci for haloperidol-induced catalepsy on mouse chromosome 14.	1999 Sep	10454512
Effect of muscarinic receptor agonists on animal models of psychosis.	2000 Apr	10893700
Estrogen priming modulates autoreceptor-mediated potentiation of dopamine uptake.	2000 Aug 11	10936494
The antidepressive-like effect of oxcarbazepine: possible role of dopaminergic neurotransmission.	2000 Jul	10871703
Effect of magnesium sulfate on the haloperidol-induced QT prolongation assessed in the canine in vivo model under the monitoring of monophasic action potential.	2000 Jun	10875735
Double blind study of tiapride versus haloperidol and placebo in agitation and aggressiveness in elderly patients with cognitive impairment.	2000 Mar	10928308
Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice.	2000 Mar 10	10720636
No changes in dopamine D(1) receptor mRNA expressing neurons in the dorsal striatum of rats with oral movements induced by long-term haloperidol administration.	2000 Mar 24	10719094
Propiverine-induced Parkinsonism: a case report and a pharmacokinetic/pharmacodynamic study in mice.	2000 May	10888308
Contrasting patterns and cellular specificity of transcriptional regulation of the nuclear receptor nerve growth factor-inducible B by haloperidol and clozapine in the rat forebrain.	2000 Oct	10987852
Effects of antipsychotic drugs on cholecystokinin and preprotachykinin (substance P) mRNA expression in the rat hippocampal formation.	2000 Sep	10974607
Haloperidol-induced impotence improved by switching to olanzapine.	2000 Sep-Oct	11203037
FosB in rat striatum: normal regional distribution and enhanced expression after 6-month haloperidol administration.	2001 Feb	11180499
Increased dopamine d(2) receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine.	2001 Feb	11156818
Double activity imaging reveals distinct cellular targets of haloperidol, clozapine and dopamine D(3) receptor selective RGH-1756.	2001 Mar	11166331

Patents

Sample Use Guides

In Vivo Use Guide

Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory.

Route of Administration: Intramuscular

In Vitro Use Guide

10 uM Haloperidol induced a 54% decrease in the mRNA expression of ABCA1 in murineperitoneal macrophages.

Name

Type

Language

HALDOL

Preferred Name

English

HALOPERIDOL

Official Name

English

EUKYSTOL

Common Name

English

HALOPERIDOL DECANOATE IMPURITY G [EP IMPURITY]

Common Name

English

VESALIUM COMPONENT HALOPERIDOL

Brand Name

English

HALOPERIDOL [HSDB]

Common Name

English

HALOPERIDOL [WHO-IP]

Common Name

English

SIGAPERIDOL

Common Name

English

KESELAN

Common Name

English

ALOPERIDIN

Common Name

English

NSC-170973

Code

English

Haloperidol [WHO-DD]

Common Name

English

HALOPERIDOL [EP MONOGRAPH]

Common Name

English

HALOPERIDOL [JAN]

Common Name

English

R-1625

Code

English

NSC-615296

Code

English

HALOPERIDOLUM [WHO-IP LATIN]

Common Name

English

SERENELFI

Common Name

English

SERENASE

Common Name

English

BIOPERIDOLO

Common Name

English

1-BUTANONE, 4-(4-(4-CHLOROPHENYL)-4-HYDROXY-1-PIPERIDINYL)-1-(4-FLUOROPHENYL)-

Systematic Name

English

HALOPERIDOL [MI]

Common Name

English

SERENACE

Common Name

English

HALOPERIDOL [USP MONOGRAPH]

Common Name

English

HALOPERIDOL DECANOATE IMPURITY, HALOPERIDOL- [USP IMPURITY]

Common Name

English

HALOPERIDOL [MART.]

Common Name

English

NEURODOL

Common Name

English

LINTON

Common Name

English

HALOPERIDOL [ORANGE BOOK]

Common Name

English

HALOPERIDOL [USP IMPURITY]

Common Name

English

HALOPERIDOL [USAN]

Common Name

English

haloperidol [INN]

Common Name

English

HALOPERIDOL [VANDF]

Common Name

English

DOZIC

Common Name

English

HALOPERIDOL [USP-RS]

Common Name

English

Classification Tree Code System Code

LIVERTOX

NBK548393