TRIFLUOPERAZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H24F3N3S
Molecular Weight	407.4974
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCN(CCCN2c3ccccc3Sc4ccc(cc42)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 283 Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2575
Dopamine D1 receptor 94 Target ID: CHEMBL2056 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2575
Dopamine D3 receptor 85 Target ID: CHEMBL234 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2575
Dopamine D4 receptor 66 Target ID: CHEMBL219 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2575

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 276 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/11-552SLR112.pdf	Primary		Approved 8043	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 8043	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 1118	inhibitor 1475

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1330 CYP1A 69 CYP2B 15 CYP2C11 4 CYP2E1 790 CYP3A2 9 BCRP 643 Kv1.3 16 Kv4.3 15 Ca2+ channels 40	UGT1A4 330 CYP1A2 972 FMO 33	CYP1A 48 CYP2B 28 CYP2C11 11 CYP2E1 117 CYP3A2 6

Drug as perpetrator

Target	Modality	Activity
CYP1A 110	inducer 1440 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP1A 110	inhibitor 3045 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 36	inducer 1440 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 36	inhibitor 3045 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 12	inducer 1440 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 12	inhibitor 3045 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 871	inducer 1440 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 871	inhibitor 3045 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 12	inducer 1440 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 12	inhibitor 3045 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
BCRP 713	inhibitor 3045 Sources: https://link.springer.com/article/10.1007/s11095-020-02954-1 Page: 230.0	yes [IC50 17.6 uM]
Kv4.3 15	inhibitor 3045 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0304394014005266 Page: abstract	yes [IC50 8 uM]
Ca2+ channels 43	inhibitor 3045 Sources: https://www.sciencedirect.com/science/article/pii/S002192581970249X Page: abstract	yes
Kv1.3 31	inhibitor 3045 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295202015617 Page: abstract	yes
P-gp 1514	inhibitor 3045 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0928098706000819 Page: abstract	yes

Drug as victim

Target	Modality	Activity
CYP2D6 1118	substrate 3113 Sources: https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1038/clpt.1993.197 Page: 607.0	likely
CYP1A2 972	substrate 3113 Sources: https://www.ingentaconnect.com/contentone/ben/cppm/2020/00000017/00000001/art00011# Page: 60.0	yes
FMO 33	substrate 3113 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295214001002 Page: 3.0	yes
UGT1A4 330	substrate 3113 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 1507	inhibitor 1489 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
Deanol in the treatment of tardive dyskinesia.	1975 Aug	1147074
Drug-induced dystonia.	1975 May	1119613
Low urinary dopamine and prediction of phenothiazine-induced Parkinsonism: a preliminary report.	1976 Jun	1275103
Drug-induced torsade de pointes.	1985 Nov-Dec	2416504
The effects of chronic treatment and withdrawal of CNS depressants on aggressive behavior.	1989 Dec	2560590
Organic amnestic disorder: a long-term sequel after neuroleptic malignant syndrome.	1991 Feb 15	2036482
Biochemical properties of a minimal functional domain with ATP-binding activity of the NTPase/helicase of hepatitis C virus.	1999 Dec	10583365
Neuroleptic malignant syndrome after venlafaxine.	2000 Jan 22	10675082
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
Voltage dependence of the [Ca2+](i) oscillations system, in the Mg2+ -stimulated oocyte of the prawn Palaemon serratus.	2001 Feb	11162847
Use of trifluoroperazine isolates a [(3)H]Ifenprodil binding site in rat brain membranes with the pharmacology of the voltage-independent ifenprodil site on N-methyl-D-aspartate receptors containing NR2B subunits.	2001 Jan	11123375
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
Calcium involvement in the luminescence control of three ophiuroid species (Echinodermata).	2002 Feb	11879782
Atypical antipsychotics: mechanism of action.	2002 Feb	11873706
Characterization of PMCA isoforms and their contribution to transcellular Ca2+ flux in MDCK cells.	2003 Jan	12388403
New agents active against Mycobacterium avium complex selected by molecular topology: a virtual screening method.	2004 Jan	14645324
Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes.	2004 Jan 9	14718172
"Wages of fear": transient threefold decrease in intracellular ATP level imposes apoptosis.	2004 Jul 23	15282185
Quaternary ammonium-linked glucuronidation of tamoxifen by human liver microsomes and UDP-glucuronosyltransferase 1A4.	2004 Jun 1	15135306
Anticataleptic effect of energostim during single treatment with trifluoperazine.	2004 Mar	15232633
Search of chemical scaffolds for novel antituberculosis agents.	2005 Apr	15809316
Delirium and extrapyramidal symptoms due to a lithium-olanzapine combination therapy: a case report.	2005 Aug	16100469
Altered inducible nitric oxide synthase expression and nitric oxide production in the bladder of cats with feline interstitial cystitis.	2005 Feb	15643277
Characterization of afloqualone N-glucuronidation: species differences and identification of human UDP-glucuronosyltransferase isoform(s).	2005 Jan	15475412
Overview and emerging trends.	2005 Oct	20711306
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
Consideration of use of phenothiazines in particular trifluorperazine for epidermal growth factor receptor associated cancers.	2007	17448610
In silico prediction of pregnane X receptor activators by machine learning approaches.	2007 Jan	17003167
Unusual case reports: Tardive oculogyric crisis (tardive syndromes).	2007 Jul	20661391
Activity and post antifungal effect of chlorpromazine and trifluopherazine against Aspergillus, Scedosporium and zygomycetes.	2007 Jul	17576318
Inflammation-related genes up-regulated in schizophrenia brains.	2007 Sep 6	17822540
Clozapine-induced tardive dystonia (blepharospasm).	2007 Winter	17308236
Pleiotropic effects of cadmium in mesangial cells.	2009 Aug 1	19233221
Spectroscopic and electrochemical analysis of psychotropic drugs.	2009 Jan	20177449
Finding my faith.	2009 Jan	19742194
Structure of the inhibitor W7 bound to the regulatory domain of cardiac troponin C.	2009 Jun 23	19419198
In vivo reorganization of the actin cytoskeleton in leaves of Nicotiana tabacum L. transformed with plastin-GFP. Correlation with light-activated chloroplast responses.	2009 May 29	19480655
Mechanism of catch force: tethering of thick and thin filaments by twitchin.	2010	20625409
Lithium, trifluperazine and idiopathic leucopenia: Author and reviewer perspectives on how to write a good case report.	2010 Apr	20838509
Acute akathisia with quetiapine: A case report and review of literature.	2010 Dec	21189919
Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.	2010 Dec	21158687
Research on antidepressants in India.	2010 Jan	21836704
Changes in clinical trials methodology over time: a systematic review of six decades of research in psychopharmacology.	2010 Mar 3	20209133
Inhibitory effect of chlorpromazine on RANKL-induced osteoclastogenesis in mouse bone marrow cells.	2011	21869564
Comparison of the effect of non-antifungal and antifungal agents on Candida isolates from the gastrointestinal tract.	2012 Jan	22208440
Regorafenib impairs mitochondrial functions, activates AMP-activated protein kinase, induces autophagy, and causes rat hepatocyte necrosis.	2015 Jan 2	25445804
In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug-drug interactions.	2015 Jan 22	25448279

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

TRIFLUOPERAZINE

Official Name

English

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

Systematic Name

English

TRIFLUOPERAZINE [WHO-DD]

Common 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 [INN]

Common Name

English

NSC-46061

Code

English

Classification Tree Code System Code

NDF-RT

N0000007544