FLUPHENAZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H26F3N3OS
Molecular Weight	437.522
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OCCN1CCN(CCCN2C3=C(SC4=C2C=C(C=C4)C(F)(F)F)C=CC=C3)CC1

InChI

InChIKey=PLDUPXSUYLZYBN-UHFFFAOYSA-N

InChI=1S/C22H26F3N3OS/c23-22(24,25)17-6-7-21-19(16-17)28(18-4-1-2-5-20(18)30-21)9-3-8-26-10-12-27(13-11-26)14-15-29/h1-2,4-7,16,29H,3,8-15H2

HIDE SMILES / InChI

Molecular Formula	C22H26F3N3OS
Molecular Weight	437.522
Charge	0
Count

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

Description
Sources: http://www.drugbank.ca/drugs/DB00623
Curator's Comment: Description was created based on several sources, including

Fluphenazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Fluphenazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. Fluphenazine 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Carboxylesterase 8 Target ID: CHEMBL3383 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9755905	Substrate 656
Dopamine D2 receptor 297 Target ID: CHEMBL217 Sources: http://www.drugbank.ca/drugs/DB00623	Antagonist 2760
Serotonin 2c (5-HT2c) receptor 122 Target ID: CHEMBL225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11561066	Inverse Agonist 79	1.412 µM [EC50]
Adrenergic receptor alpha-1 169 Target ID: CHEMBL1907610 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2879204	Antagonist 2760
Dopamine D1 receptor 101 Target ID: CHEMBL2056 Sources: http://www.drugbank.ca/drugs/DB00623	Antagonist 2760

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 295 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/071413s019lbl.pdf	Primary		Approved 8360	FLUPHENAZINE DECANOATE Approved Use Fluphenazine Decanoate Injection is a longacting parenteral antipsychotic drug intended for use in the management of patients requiring prolonged parenteral neuroleptic therapy (e.g., chronic schizophrenics). Launch Date 5.5313282E11

C_max

Value	Dose	Analyte	Population
2.3 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	12 mg single, oral dose: 12 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
261 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	2.5 mg 3 times / 3 days multiple, intravenous dose: 2.5 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
0.52 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2313572	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
6.92 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2313572	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		FLUPHENAZINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
14.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	12 mg single, oral dose: 12 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12.3 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	2.5 mg 3 times / 3 days multiple, intravenous dose: 2.5 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
13 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2313572	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.6% EXPERIMENT https://www.agilent.com/cs/library/applications/5991-2497EN.pdf			FLUPHENAZINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	Disc. AE: Akathisia, Dyskinesia... AEs leading to discontinuation/dose reduction: Akathisia (3.3%) Dyskinesia (3.3%) Hypertonia (3.3%) Stupor (3.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
250 mg 1 times / week multiple, intramuscular Highest studied dose Dose: 250 mg, 1 times / week Route: intramuscular Route: multiple Dose: 250 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/11760 Page: p.1438	unhealthy, 44 n = 25 Health Status: unhealthy Condition: Schizophrenia Age Group: 44 Sex: M+F Population Size: 25 Sources: https://pubmed.ncbi.nlm.nih.gov/11760 Page: p.1438	Sources: https://pubmed.ncbi.nlm.nih.gov/11760 Page: p.1438
100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	Disc. AE: Tardive dyskinesia, Neuroleptic malignant syndrome... AEs leading to discontinuation/dose reduction: Tardive dyskinesia Neuroleptic malignant syndrome Fall Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display

AEs

AE	Significance	Dose	Population
Akathisia	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Dyskinesia	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Hypertonia	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Stupor	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Fall	Disc. AE	100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display
Neuroleptic malignant syndrome	Disc. AE	100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display
Tardive dyskinesia	Disc. AE	100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1709 inhibitor 1579	inhibitor 1752	substrate 1193 inhibitor 1837	inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1509	CYP2C19 985

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1673	inhibitor 3240 Sources: https://dmd.aspetjournals.org/content/27/9/1078.short	moderate [Ki 40.2 uM]
CYP2C9 1803	inhibitor 3240 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0009279704000250 Page: 5.0	weak [IC50 398.1 uM]
CYP3A4 1909	inhibitor 3240 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0009279704000250 Page: 5.0	weak [IC50 441.2 uM]
CYP2D6 1875	inhibitor 3240 Sources: https://dmd.aspetjournals.org/content/27/9/1078.short	yes [Ki 9.4 uM]

Drug as victim

Target	Modality	Activity
CYP2C19 985	substrate 3326 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes
CYP2D6 1193	substrate 3326 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes
CYP3A4 1709	substrate 3326 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1632	inhibitor 1613 Sources: https://pubmed.ncbi.nlm.nih.gov/23395964/ Page: 7.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:5123	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:5123
ChemicalBook	CB7107784	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7107784
MolPort	MolPort-001-727-938	https://www.molport.com/shop/molecule-link/MolPort-001-727-938
ZINC	ZINC000019203912	http://zinc15.docking.org/substances/ZINC000019203912
eMolecules	732810	https://www.emolecules.com/cgi-bin/more?vid=732810

PubMed

Title	Date	PubMed
Dystonic reactions to phenothiazine derivatives.	1966 Oct	5957732
Treatment of resistant schizophrenics with extreme high dosage fluphenazine hydrochloride.	1970 Sep-Oct	4919176
Maintenance treatment of schizophrenia with long-acting fluphenazine.	1974 Aug	4154028
Phenothiazine-induced decompensation.	1974 Jan	4587065
The effect of 5-hydroxytrytamine synthesis inhibitors on neuroleptic-induced catalepsy in rats.	1975	1172422
Dystonic reaction to high dose propranolol.	1977 Oct 29	589060
High vs standard dosage fluphenazine HCL in acute schizophrenia.	1978 Nov	363702
The influence of alpha-adrenergic drugs on catalepsy induced by haloperidol or fluphenazine in rats.	1978 Sep-Oct	35783
Sleep disturbance associated with fluphenazine HCl: a case report.	1979 Jul	453364
Benztropine prophylaxis of dystonic reactions.	1979 Mar 28	36644
Delirium associated with combined fluphenazine-clonidine therapy.	1979 May	438148
Neuroleptic-induced acute dyskinesias in rhesus monkeys.	1981	6117919
Intrauterine effect of phenothiazines.	1981 Apr 18	7254089
Neuroleptic-induced seizures. An in vitro technique for assessing relative risk.	1982 Feb	6175290
Occurrence of neuroleptic malignant syndrome in a narcoleptic patient.	1983 Jun	6134661
Neuroleptic malignant syndrome.	1984 Jan 7	6146918
Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes.	1984 Sep	6147851
[Catatonia due to fluphenazine].	1986 Apr 1	3732946
Drug-induced dystonia in young and elderly patients.	1988 Jul	2898212
Manic syndrome associated with zidovudine treatment.	1988 Jun 17	3163740
Prolonged fever without extrapyramidal symptoms during neuroleptic treatment.	1989 Jun	2738187
Propranolol withdrawal in psychosis.	1990 Apr	2316745
Fluphenazine dose, clinical response, and extrapyramidal symptoms during acute treatment.	1990 Aug	2378547
Affective disorder following use of phenylpropanolamine.	1990 Mar	2309957
Blockade of both D-1 and D-2 dopamine receptors may induce catalepsy in mice.	1991	1687392
Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1.	1991 Apr 18	1826762
Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors.	1994 Mar	7908055
Some behavioral effects of CNQX AND NBQX, AMPA receptor antagonists.	1995 Jul-Aug	8616504
Fluphenazine plasma levels, dosage, efficacy, and side effects.	1995 May	7726317
Some central effects of GYKI 52466, a non-competitive AMPA receptor antagonist.	1995 Nov-Dec	8868372
Roxindole, a potential antidepressant. I. Effect on the dopamine system.	1996	8811507
Tardive dyskinesia induced by risperidone?	1996 Jun	8633711
Case report of withdrawal syndrome after olanzapine discontinuation.	2000 Aug	10917413
Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans.	2000 Sep	10952582
H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs.	2003 Mar	12629531
Analysis of phenothiazine and its derivatives using LC/electrochemistry/MS and LC/electrochemistry/fluorescence.	2003 Sep 15	14674461
Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior.	2004 Feb 18	14973230
Stable expression of constitutively activated mutant h5HT6 and h5HT7 serotonin receptors: inverse agonist activity of antipsychotic drugs.	2005 May	15821958
Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers.	2005 Sep 1	16005384
[Trazodone for the treatment of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease: a retrospective study focused on the aggression and negativism in caregiving situations].	2006 Jun	16856516
Dopamine antagonist alters serum cortisol and prolactin secretion in lactating Holstein cows.	2006 Jun	16702268
Hybrid approach for the design of highly affine and selective dopamine D(3) receptor ligands using privileged scaffolds of biogenic amine GPCR ligands.	2007 Dec 1	17826096
Neuroleptic-induced dysphagia: case report and literature review.	2007 Jan	17024549
In silico prediction of pregnane X receptor activators by machine learning approaches.	2007 Jan	17003167
Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.	2007 Jul 17	17606915
Chronic treatment with fluphenazine alters parameters of oxidative stress in liver and kidney of rats.	2009 Jul	19486337
An insight into the sialotranscriptome of the brown dog tick, Rhipicephalus sanguineus.	2010 Jul 22	20650005
[A case of drug-induced syndrome of inappropriate secretion of antidiuretic hormone].	2010 Jul-Aug	20672238
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003
Antitubercular pharmacodynamics of phenothiazines.	2013 Apr	23228936

Patents

Sample Use Guides

In Vivo Use Guide

For most patients, a dose of 12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy.

Route of Administration: Intramuscular

In Vitro Use Guide

30uM Fluphenazine inhibited the high-threshold Ca2 channel current in rat sympathetic neurons (blocking by 66%).

Substance Class	Chemical Created by `admin` on `Wed Jul 05 23:59:29 UTC 2023` Edited by `admin` on `Wed Jul 05 23:59:29 UTC 2023`
Record UNII	S79426A41Z
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

FLUPHENAZINE

Official Name

English

FLUPHENAZINE ENANTHATE IMPURITY B [EP IMPURITY]

Common Name

English

1-PIPERAZINEETHANOL, 4-(3-(2-(TRIFLUOROMETHYL)-10H-PHENOTHIAZIN-10-YL)PROPYL)-

Systematic Name

English

NSC-62323

Code

English

FLUPHENAZINE [MART.]

Common Name

English

FLUPHENAZINE [MI]

Common Name

English

FLUPHENAZINE ENANTATE IMPURITY B [EP IMPURITY]

Common Name

English

4-(3-(2-(TRIFLUOROMETHYL)PHENOTHIAZIN-10-YL)PROPYL)-1-PIPERAZINEETHANOL

Systematic Name

English

Fluphenazine [WHO-DD]

Common Name

English

FLUPHENAZINE [HSDB]

Common Name

English

fluphenazine [INN]

Common Name

English

FLUPHENAZINE [VANDF]

Common Name

English

MODITEN

Brand Name

English

FLUPHENAZINE DECANOATE IMPURITY B [EP IMPURITY]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000007544