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=C2C=CC=C4)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

Molecular Formula	C21H24F3N3S
Molecular Weight	407.496
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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 297 Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2760
Dopamine D1 receptor 101 Target ID: CHEMBL2056 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2760
Dopamine D3 receptor 91 Target ID: CHEMBL234 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2760
Dopamine D4 receptor 71 Target ID: CHEMBL219 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2760

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 295 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/11-552SLR112.pdf	Primary		Approved 8360	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 -3.38083185E11
Non psychotic anxiety 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/11-552SLR112.pdf	Primary		Approved 8360	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 -3.38083185E11

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 1193	inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1437 CYP1A 72 CYP2B 15 CYP2C11 4 CYP2E1 876 CYP3A2 10 BCRP 691 Kv1.3 17 Kv4.3 16 Ca2+ channels 41	UGT1A4 347 CYP1A2 1032 FMO 35	CYP1A 56 CYP2B 32 CYP2C11 14 CYP2E1 126 CYP3A2 6

Drug as perpetrator

Target	Modality	Activity
CYP1A 121	inducer 1542 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP1A 121	inhibitor 3240 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 40	inducer 1542 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 40	inhibitor 3240 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 15	inducer 1542 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 15	inhibitor 3240 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 964	inducer 1542 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 964	inhibitor 3240 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 13	inducer 1542 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 13	inhibitor 3240 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
BCRP 765	inhibitor 3240 Sources: https://link.springer.com/article/10.1007/s11095-020-02954-1 Page: 230.0	yes [IC50 17.6 uM]
Kv4.3 16	inhibitor 3240 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0304394014005266 Page: abstract	yes [IC50 8 uM]
Ca2+ channels 44	inhibitor 3240 Sources: https://www.sciencedirect.com/science/article/pii/S002192581970249X Page: abstract	yes
Kv1.3 32	inhibitor 3240 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295202015617 Page: abstract	yes
P-gp 1626	inhibitor 3240 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0928098706000819 Page: abstract	yes

Drug as victim

Target	Modality	Activity
CYP2D6 1193	substrate 3326 Sources: https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1038/clpt.1993.197 Page: 607.0	likely
CYP1A2 1032	substrate 3326 Sources: https://www.ingentaconnect.com/contentone/ben/cppm/2020/00000017/00000001/art00011# Page: 60.0	yes
FMO 35	substrate 3326 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295214001002 Page: 3.0	yes
UGT1A4 347	substrate 3326 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 1632	inhibitor 1613 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
MolPort	MolPort-001-727-956	https://www.molport.com/shop/molecule-link/MolPort-001-727-956
ZINC	ZINC000019418959	http://zinc15.docking.org/substances/ZINC000019418959
eMolecules	730268	https://www.emolecules.com/cgi-bin/more?vid=730268

PubMed

Title	Date	PubMed
The antinicotinic effects of drugs with clinically useful sedative-antianxiety properties.	1975	1803
Low urinary dopamine and prediction of phenothiazine-induced Parkinsonism: a preliminary report.	1976 Jun	1275103
Extra pyramidal side effects associated with paroxetine.	1992 Dec	1308691
Antitubercular activity of trifluoperazine, a calmodulin antagonist.	1992 Oct 1	1427006
Fits and starts.	1998 Nov	10197221
In vitro susceptibility testing of Mycobacterium tuberculosis strains to trifluoperazine.	1999 Jun	10435682
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
Atypical antipsychotics: mechanism of action.	2002 Feb	11873706
Novel protein kinase induced during sporangial cleavage in the oomycete Phytophthora infestans.	2002 Oct	12455688
Characterization of PMCA isoforms and their contribution to transcellular Ca2+ flux in MDCK cells.	2003 Jan	12388403
Acute dystonia caused by low dosage of olanzapine.	2003 Spring	12724469
New agents active against Mycobacterium avium complex selected by molecular topology: a virtual screening method.	2004 Jan	14645324
Altered inducible nitric oxide synthase expression and nitric oxide production in the bladder of cats with feline interstitial cystitis.	2005 Feb	15643277
Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates.	2005 Nov	16251329
Steady-state kinetics and inhibitory action of antitubercular phenothiazines on mycobacterium tuberculosis type-II NADH-menaquinone oxidoreductase (NDH-2).	2006 Apr 28	16469750
Hydrogen peroxide inhibits IL-12 p40 induction in macrophages by inhibiting c-rel translocation to the nucleus through activation of calmodulin protein.	2006 Feb 15	16249388
Effect of the flavonol quercetin on ion transport in the isolated intestine of the eel, Anguilla anguilla.	2006 May	16466967
In silico prediction of pregnane X receptor activators by machine learning approaches.	2007 Jan	17003167
Agricultural exposures and gastric cancer risk in Hispanic farm workers in California.	2007 Jun	17196584
Clozapine-induced tardive dystonia (blepharospasm).	2007 Winter	17308236
Physiological hydrostatic pressure protects endothelial monolayer integrity.	2008 Jan	17977944
Interaction of antagonists with calmodulin: insights from molecular dynamics simulations.	2008 Jun 12	18459732
Finding my faith.	2009 Jan	19742194
Structure of the inhibitor W7 bound to the regulatory domain of cardiac troponin C.	2009 Jun 23	19419198
The story of antipsychotics: Past and present.	2009 Oct-Dec	20048463
Mechanism of catch force: tethering of thick and thin filaments by twitchin.	2010	20625409
Allosteric effects of the antipsychotic drug trifluoperazine on the energetics of calcium binding by calmodulin.	2010 Aug 1	20544963
Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.	2010 Dec	21158687
A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle.	2010 Feb 23	20142494
Inhibitory effect of chlorpromazine on RANKL-induced osteoclastogenesis in mouse bone marrow cells.	2011	21869564
Terpenoids inhibit Candida albicans growth by affecting membrane integrity and arrest of cell cycle.	2011 Oct 15	21596542
Comparison of the effect of non-antifungal and antifungal agents on Candida isolates from the gastrointestinal tract.	2012 Jan	22208440
A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis.	2013 Feb	23243064
Phenothiazines inhibit hepatitis C virus entry, likely by increasing the fluidity of cholesterol-rich membranes.	2013 Jun	23529728

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.

Substance Class	Chemical Created by `admin` on `Wed Jul 05 22:40:38 UTC 2023` Edited by `admin` on `Wed Jul 05 22:40:38 UTC 2023`
Record UNII	214IZI85K3
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

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

APO-TRIFLUOPERAZINE

Brand 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