TRIFLUOPERAZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H24F3N3S
Molecular Weight	407.496
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCN(CCCN2C3=CC=CC=C3SC4=CC=C(C=C24)C(F)(F)F)CC1

InChI

InChIKey=ZEWQUBUPAILYHI-UHFFFAOYSA-N

InChI=1S/C21H24F3N3S/c1-25-11-13-26(14-12-25)9-4-10-27-17-5-2-3-6-19(17)28-20-8-7-16(15-18(20)27)21(22,23)24/h2-3,5-8,15H,4,9-14H2,1H3

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/11-552SLR112.pdf
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB00831 | https://www.drugs.com/cdi/trifluoperazine.html | https://clinicaltrials.gov/ct2/show/NCT02600741 | http://reference.medscape.com/drug/trifluoperazine-342991

Trifluoperazine (Eskazinyl, Eskazine, Jatroneural, Modalina, Stelazine, Terfluzine, Trifluoperaz, Triftazin) is a typical antipsychotic of the phenothiazine chemical class used for the short-term treatment of certain types of anxiety. Trifluoperazine 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. The primary application of trifluoperazine is for schizophrenia. Other official indications may vary country by country, but generally, it is also indicated for use in agitation and patients with behavioral problems, severe nausea, and vomiting as well as severe anxiety. Trials have shown a moderate benefit of this drug in patients with borderline personality disorder. A 2004 meta-analysis of the studies on trifluoperazine found that it is more likely than placebo to cause extrapyramidal side effects such as akathisia, dystonia, and Parkinsonism. It is also more likely to cause somnolence and anticholinergic side effects such as red-eye and xerostomia (dry mouth).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dopamine D2 receptor 311 Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2849
Dopamine D1 receptor 106 Target ID: CHEMBL2056 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2849
Dopamine D3 receptor 97 Target ID: CHEMBL234 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2849
Dopamine D4 receptor 76 Target ID: CHEMBL219 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2849

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 305 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/11-552SLR112.pdf	Primary		Approved 8583	STELAZINE Approved Use For the management of schizophrenia. Trifluoperazine HCl is effective for the short-term treatment of generalized non-psychotic anxiety. However, trifluoperazine HCl is not the first drug to be used in therapy for most patients with non-psychotic anxiety because certain risks associated with its use are not shared by common alternative treatments (i.e., benzodiazepines). When used in the treatment of non-psychotic anxiety, trifluoperazine HCl should not be administered at doses of more than 6 mg per day or for longer than 12 weeks because the use of trifluoperazine HCl at higher doses or for longer intervals may cause persistent tardive dyskinesia that may prove irreversible (see WARNINGS ). The effectiveness of trifluoperazine HCl as a treatment for non-psychotic anxiety was established in a four-week clinical multicenter study of outpatients with generalized anxiety disorder (DSM-III). This evidence does not predict that trifluoperazine HCl will be useful in patients with other non-psychotic conditions in which anxiety, or signs that mimic anxiety, are found (i.e., physical illness, organic mental conditions, agitated depression, character pathologies, etc.). Trifluoperazine HCl has not been shown effective in the management of behavioral complications in patients with mental retardation. Launch Date 1959
Non psychotic anxiety 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/11-552SLR112.pdf	Primary		Approved 8583	STELAZINE Approved Use For the management of schizophrenia. Trifluoperazine HCl is effective for the short-term treatment of generalized non-psychotic anxiety. However, trifluoperazine HCl is not the first drug to be used in therapy for most patients with non-psychotic anxiety because certain risks associated with its use are not shared by common alternative treatments (i.e., benzodiazepines). When used in the treatment of non-psychotic anxiety, trifluoperazine HCl should not be administered at doses of more than 6 mg per day or for longer than 12 weeks because the use of trifluoperazine HCl at higher doses or for longer intervals may cause persistent tardive dyskinesia that may prove irreversible (see WARNINGS ). The effectiveness of trifluoperazine HCl as a treatment for non-psychotic anxiety was established in a four-week clinical multicenter study of outpatients with generalized anxiety disorder (DSM-III). This evidence does not predict that trifluoperazine HCl will be useful in patients with other non-psychotic conditions in which anxiety, or signs that mimic anxiety, are found (i.e., physical illness, organic mental conditions, agitated depression, character pathologies, etc.). Trifluoperazine HCl has not been shown effective in the management of behavioral complications in patients with mental retardation. Launch Date 1959

C_max

Value	Dose	Co-administered	Analyte	Population
1.053 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3137618	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIFLUOPERAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
10.144 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3137618	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIFLUOPERAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
12.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3137618	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIFLUOPERAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
		substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1741 CYP1A 70 CYP2B 16 CYP2C11 4 CYP2E1 1060 CYP3A2 10 BCRP 910 Kv1.3 15 Kv4.3 16 Ca2+ channels 59	UGT1A4 399 CYP1A2 1197 FMO 34	CYP1A 59 CYP2B 32 CYP2C11 14 CYP2E1 131 CYP3A2 6

Drug as perpetrator

Target	Modality	Activity
CYP1A 122	inducer 1966 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP1A 122	inhibitor 4027 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 41	inducer 1966 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 41	inhibitor 4027 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 15	inducer 1966 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 15	inhibitor 4027 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 1146	inducer 1966 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 1146	inhibitor 4027 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 13	inducer 1966 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 13	inhibitor 4027 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
BCRP 985	inhibitor 4027 Sources: https://link.springer.com/article/10.1007/s11095-020-02954-1 Page: 230.0	yes [IC50 17.6 uM]
Kv4.3 16	inhibitor 4027 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0304394014005266 Page: abstract	yes [IC50 8 uM]
Ca2+ channels 62	inhibitor 4027 Sources: https://www.sciencedirect.com/science/article/pii/S002192581970249X Page: abstract	yes
Kv1.3 30	inhibitor 4027 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295202015617 Page: abstract	yes
P-gp 1932	inhibitor 4027 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0928098706000819 Page: abstract	yes

Drug as victim

Target	Modality	Activity
CYP2D6 1388	substrate 4014 Sources: https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1038/clpt.1993.197 Page: 607.0	likely
CYP1A2 1197	substrate 4014 Sources: https://www.ingentaconnect.com/contentone/ben/cppm/2020/00000017/00000001/art00011# Page: 60.0	yes
FMO 34	substrate 4014 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295214001002 Page: 3.0	yes
UGT1A4 399	substrate 4014 Sources: https://www.jstage.jst.go.jp/article/dmpk/25/1/25_1_16/_article/-char/ja/ Page: 24.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1038/sj.bjp.0707356 Page: 1369.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45951	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45951
ChemicalBook	CB9444115	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9444115
eMolecules	730268	https://www.emolecules.com/cgi-bin/more?vid=730268
MolPort	MolPort-001-727-956	https://www.molport.com/shop/molecule-link/MolPort-001-727-956
ZINC	ZINC000019418959	http://zinc15.docking.org/substances/ZINC000019418959

PubMed

Title	Date	PubMed
The antinicotinic effects of drugs with clinically useful sedative-antianxiety properties.	1975	1803
Trifluoroperazine for the symptomatic treatment of chorea.	1975 Mar	122926
Low urinary dopamine and prediction of phenothiazine-induced Parkinsonism: a preliminary report.	1976 Jun	1275103
Neuroleptic malignant syndrome after venlafaxine.	2000 Jan 22	10675082
Block of rat brain recombinant SK channels by tricyclic antidepressants and related compounds.	2000 Jul 28	10915830
A new potent calmodulin antagonist with arylalkylamine structure: crystallographic, spectroscopic and functional studies.	2000 Mar 31	10731425
Calmodulin antagonists inhibit T-type Ca(2+) currents in mouse spermatogenic cells and the zona pellucida-induced sperm acrosome reaction.	2001 Aug 1	11456455
Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy.	2001 May	11328759
Characterization of afloqualone N-glucuronidation: species differences and identification of human UDP-glucuronosyltransferase isoform(s).	2005 Jan	15475412
Control of hepatitis C: a medicinal chemistry perspective.	2005 Jan 13	15633995
"Calm, but still alert": Marketing Stelazine to disturbed America, 1958-1980.	2008	19831020
Miscellaneous.	2008 Oct	21593974
Research on antipsychotics in India.	2010 Jan	21836703
Changes in clinical trials methodology over time: a systematic review of six decades of research in psychopharmacology.	2010 Mar 3	20209133

Patents

Sample Use Guides

In Vivo Use Guide

Initial: 2-5 mg PO q12hr Maintenance Dose: 15-20 mg/day Not to exceed 40mg/day

Route of Administration: Oral

In Vitro Use Guide

Log-phase suspension cultures of P388/S and P388/R cells were treated with ADR (Adriamycin) (0.01 to 5.0 mkg/ml) in the presence and absence of 4 mkM TFP (Trifluoperazine ) for 24 hr at 37C. Cell counts in control and treated cultures were then determined by trypan blue dye exclusion in a hemacytometer.

Name

Type

Language

APO-TRIFLUOPERAZINE

Preferred Name

English

TRIFLUOPERAZINE

Official Name

English

PHENOTHIAZINE, 10-(3-(4-METHYL-1-PIPERAZINYL)PROPYL)-2-(TRIFLUOROMETHYL)-

Systematic Name

English

TRIFLUOPERAZINE [MI]

Common Name

English

TRIFLUOPERAZINE [VANDF]

Common Name

English

TRIFLUOPERAZINE [HSDB]

Common Name

English

FLURAZINE

Brand Name

English

NSC-17474

Code

English

RP-7623

Code

English

10H-PHENOTHIAZINE, 10-(3-(4-METHYL-1-PIPERAZINYL)PROPYL)-2-(TRIFLUOROMETHYL)-

Systematic Name

English

Trifluoperazine [WHO-DD]

Common Name

English

trifluoperazine [INN]

Common Name

English

NSC-46061

Code

English

Classification Tree Code System Code

NDF-RT

N0000007544