FLUPHENAZINE MALEATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H26F3N3OS.C4H4O4
Molecular Weight	553.594
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C/C(O)=O.OCCN1CCN(CCCN2C3=C(SC4=C2C=C(C=C4)C(F)(F)F)C=CC=C3)CC1

InChI

InChIKey=NKGQWGWZXIYMHO-BTJKTKAUSA-N

InChI=1S/C22H26F3N3OS.C4H4O4/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;5-3(6)1-2-4(7)8/h1-2,4-7,16,29H,3,8-15H2;1-2H,(H,5,6)(H,7,8)/b;2-1-

HIDE SMILES / InChI

Molecular Formula	C4H4O4
Molecular Weight	116.0722
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

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 661
Dopamine D2 receptor 297 Target ID: CHEMBL217 Sources: http://www.drugbank.ca/drugs/DB00623	Antagonist 2778
Serotonin 2c (5-HT2c) receptor 124 Target ID: CHEMBL225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11561066	Inverse Agonist 80	1.412 µM [EC50]
Adrenergic receptor alpha-1 169 Target ID: CHEMBL1907610 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2879204	Antagonist 2778
Dopamine D1 receptor 101 Target ID: CHEMBL2056 Sources: http://www.drugbank.ca/drugs/DB00623	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 298 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/071413s019lbl.pdf	Primary		Approved 8429	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 1987

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 1737 inhibitor 1587	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524	CYP2C19 991

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/27/9/1078.short	moderate [Ki 40.2 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0009279704000250 Page: 5.0	weak [IC50 398.1 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0009279704000250 Page: 5.0	weak [IC50 441.2 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/27/9/1078.short	yes [Ki 9.4 uM]

Drug as victim

Target	Modality	Activity
CYP2C19 991	substrate 3367 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes
CYP2D6 1217	substrate 3367 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes
CYP3A4 1737	substrate 3367 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 1647	inhibitor 1626 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
Side-effects of phenothiazines.	1967 Apr 1	6021008
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
High vs standard dosage fluphenazine HCL in acute schizophrenia.	1978 Nov	363702
Fluphenazine pharmacokinetics and therapeutic response.	1981	6787637
Stuttering: an unusual side effect of phenothiazines.	1981 Mar	6110346
[Malignant neuroleptics syndrome].	1984 Mar 9	6697897
[Catatonia due to fluphenazine].	1986 Apr 1	3732946
Manic syndrome associated with zidovudine treatment.	1988 Jun 17	3163740
Prolonged fever without extrapyramidal symptoms during neuroleptic treatment.	1989 Jun	2738187
Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease.	1990	1977408
Actions of ORG 5222 as a novel psychotropic agent.	1990 Mar	2111028
Evidence for an involvement of D1 and D2 dopamine receptors in mediating nicotine-induced hyperactivity in rats.	1991	1833784
On the selection of mice for haloperidol response and non-response.	1991	1827527
Relation of plasma fluphenazine levels to treatment response and extrapyramidal side effects in first-episode schizophrenic patients.	1994 Jan	8267132
Roxindole, a potential antidepressant. I. Effect on the dopamine system.	1996	8811507
The anticataleptic effect of 7-OH-DPAT: are dopamine D3 receptors involved?	1999	10651103
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
Olanzapine versus fluphenazine in an open trial in patients with psychotic combat-related post-traumatic stress disorder.	2004 Oct	15064916
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
In silico prediction of pregnane X receptor activators by machine learning approaches.	2007 Jan	17003167
Effects of omega-3 essential fatty acids (omega-3 EFAs) on motor disorders and memory dysfunction typical neuroleptic-induced: behavioral and biochemical parameter.	2010 Apr	19644727
[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

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 `Sat Dec 16 01:46:39 GMT 2023` Edited by `admin` on `Sat Dec 16 01:46:39 GMT 2023`
Record UNII	97151695PW
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

FLUPHENAZINE MALEATE

Common Name

English

FLUPHENAZINE MALEATE [JAN]

Common Name

English

2-(4-(3-(2-(TRIFLUOROMETHYL)PHENOTHIAZIN-10-YL)PROPYL)PIPERAZIN-1-YL)ETHANOL (Z)-BUT-2-ENEDIOIC ACID (1:1)

Systematic Name

English

Fluphenazine maleate [WHO-DD]

Common Name

English

FLUOROPHENAZINE MALEATE

Systematic Name

English

Code System Code Type Description

ChEMBL

CHEMBL1200951