TRIFLUOPERAZINE HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H24F3N3S.2ClH
Molecular Weight	480.417
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of TRIFLUOPERAZINE HYDROCHLORIDE

Structure Search

SMILES

Cl.Cl.CN1CCN(CCCN2C3=C(SC4=C2C=C(C=C4)C(F)(F)F)C=CC=C3)CC1

InChI

InChIKey=BXDAOUXDMHXPDI-UHFFFAOYSA-N

InChI=1S/C21H24F3N3S.2ClH/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;2*1H

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 297 Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2778
Dopamine D1 receptor 101 Target ID: CHEMBL2056 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2778
Dopamine D3 receptor 91 Target ID: CHEMBL234 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2778
Dopamine D4 receptor 71 Target ID: CHEMBL219 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26372073	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 298 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/11-552SLR112.pdf	Primary		Approved 8429	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 8429	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 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP1A 72 CYP2B 15 CYP2C11 4 CYP2E1 882 CYP3A2 10 BCRP 699 Kv1.3 17 Kv4.3 16 Ca2+ channels 57	UGT1A4 347 CYP1A2 1054 FMO 35	CYP1A 56 CYP2B 32 CYP2C11 14 CYP2E1 128 CYP3A2 6

Drug as perpetrator

Target	Modality	Activity
CYP1A 121	inducer 1573 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP1A 121	inhibitor 3277 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 40	inducer 1573 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2B 40	inhibitor 3277 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 15	inducer 1573 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2C11 15	inhibitor 3277 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 970	inducer 1573 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP2E1 970	inhibitor 3277 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 13	inducer 1573 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
CYP3A2 13	inhibitor 3277 Sources: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0773.1999.tb02018.x Page: abstract	no
BCRP 773	inhibitor 3277 Sources: https://link.springer.com/article/10.1007/s11095-020-02954-1 Page: 230.0	yes [IC50 17.6 uM]
Kv4.3 16	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0304394014005266 Page: abstract	yes [IC50 8 uM]
Ca2+ channels 60	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/pii/S002192581970249X Page: abstract	yes
Kv1.3 32	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295202015617 Page: abstract	yes
P-gp 1650	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0928098706000819 Page: abstract	yes

Drug as victim

Target	Modality	Activity
CYP2D6 1217	substrate 3367 Sources: https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1038/clpt.1993.197 Page: 607.0	likely
CYP1A2 1054	substrate 3367 Sources: https://www.ingentaconnect.com/contentone/ben/cppm/2020/00000017/00000001/art00011# Page: 60.0	yes
FMO 35	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0006295214001002 Page: 3.0	yes
UGT1A4 347	substrate 3367 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 1647	inhibitor 1626 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
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
Pseudo-tetanus following trifluoperazine.	1990 Oct	2278124
Association of high prolactin levels and neuroleptics immediately postpartum.	1990 Winter	2136057
On the selection of mice for haloperidol response and non-response.	1991	1827527
Organic amnestic disorder: a long-term sequel after neuroleptic malignant syndrome.	1991 Feb 15	2036482
Pisa syndrome in an adolescent on neuroleptic medication.	1991 Mar	2036543
Folie à deux.	2005 Jul	20814461
Overview and emerging trends.	2005 Oct	20711306
Endogenous zinc in neurological diseases.	2005 Oct	20396459
Treatment of generalized anxiety disorder.	2007 Apr	19300551
Unusual case reports: Tardive oculogyric crisis (tardive syndromes).	2007 Jul	20661391
Comment on 'Topical verapamil HCL, topical trifluoroperazine, and topical magnesium sulfate for the treatment of Peyronie's disease--a placebo-controlled pilot study'.	2007 Jul	17627753
Inflammation-related genes up-regulated in schizophrenia brains.	2007 Sep 6	17822540
"Calm, but still alert": Marketing Stelazine to disturbed America, 1958-1980.	2008	19831020
Role of TRP channels and NCX in mediating hypoxia-induced [Ca(2+)](i) elevation in PC12 cells.	2008 Dec 31	18822394
Physiological hydrostatic pressure protects endothelial monolayer integrity.	2008 Jan	17977944
Preservation of protein clefts in comparative models.	2008 Jan 16	18199319
Interaction of antagonists with calmodulin: insights from molecular dynamics simulations.	2008 Jun 12	18459732
Miscellaneous.	2008 Oct	21593974
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
A molecular model for diacylglycerol acyltransferase from Mortierella ramanniana var. angulispora.	2009 Jun 28	19759814
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
The story of antipsychotics: Past and present.	2009 Oct-Dec	20048463
Molecular mechanism of trifluoperazine induces apoptosis in human A549 lung adenocarcinoma cell lines.	2009 Sep-Oct	21475906
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
Allosteric effects of the antipsychotic drug trifluoperazine on the energetics of calcium binding by calmodulin.	2010 Aug 1	20544963
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
A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle.	2010 Feb 23	20142494
Research on antidepressants in India.	2010 Jan	21836704
Research on antipsychotics in India.	2010 Jan	21836703
Anti-psychotic prescription pattern: A preliminary survey of Psychiatrists in India.	2010 Jul	21180412
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
Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network.	2011 Apr 22	21544200
Terpenoids inhibit Candida albicans growth by affecting membrane integrity and arrest of cell cycle.	2011 Oct 15	21596542
Activity of trifluoperazine against replicating, non-replicating and drug resistant M. tuberculosis.	2012	22952939
Comparison of the effect of non-antifungal and antifungal agents on Candida isolates from the gastrointestinal tract.	2012 Jan	22208440
Antitubercular pharmacodynamics of phenothiazines.	2013 Apr	23228936
Avermectin induces P-glycoprotein expression in S2 cells via the calcium/calmodulin/NF-κB pathway.	2013 Apr 25	23523950
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
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 HYDROCHLORIDE

Common Name

English

10-[3-(4-Methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine dihydrochloride

Systematic Name

English

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

Common Name

English

TRIFLUOPERAZINE HYDROCHLORIDE [MART.]

Common Name

English

STELAZINE

Brand Name

English

TRIFLUOPERAZINE DIHYDROCHLORIDE

Common Name

English

TRIFLUOPERAZINE HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

TRIFLUOPERAZINE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

TRIFLUOPERAZINE HYDROCHLORIDE [USP-RS]

Common Name

English

TRIFLUOPERAZINE HCL

Common Name

English

NSC-757369

Code

English

TRIFLUOPERAZINE HYDROCHLORIDE [EP MONOGRAPH]

Common Name

English

TRIFLUOPERAZINE HYDROCHLORIDE [VANDF]

Common Name

English

Trifluoperazine hydrochloride [WHO-DD]

Common Name

English

TRIFLUOPERAZINE HYDROCHLORIDE [JAN]

Common Name

English

TRIFLUOPERAZINE DIHYDROCHLORIDE [MI]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C740