PERPHENAZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H26ClN3OS
Molecular Weight	403.969
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

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

InChI

InChIKey=RGCVKNLCSQQDEP-UHFFFAOYSA-N

InChI=1S/C21H26ClN3OS/c22-17-6-7-21-19(16-17)25(18-4-1-2-5-20(18)27-21)9-3-8-23-10-12-24(13-11-23)14-15-26/h1-2,4-7,16,26H,3,8-15H2

HIDE SMILES / InChI

Molecular Formula	C21H26ClN3OS
Molecular Weight	403.969
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

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

Description

Perphenazine is a relatively high potency phenothiazine that blocks dopamine 2 receptors predominantly, but also may possess antagonist actions at histamine 1 and cholinergic M1 and alpha 1 adrenergic receptors in the vomiting center leading to reduced nausea and vomiting. The drug was approved by FDA for the treatment of schizophrenia and control of severe nausea and vomiting (either alone or in combination with amitriptyline hydrochloride). Perphenazine is extensively hepatic to metabolites via sulfoxidation, hydroxylation, dealkylation, and glucuronidation; primarily metabolized by CYP2D6 to N-dealkylated perphenazine, perphenazine sulfoxide, and 7-hydroxyperphenazine (active metabolite with 70% of the activity of perphenazine) and excreted in the urine and feces.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Potency
D(2) dopamine receptor 58	Antagonist 2,778	0.16 nM [Ki]
Histamine H1 receptor 315	Antagonist 2,778	8.0 nM [Kd]
Muscarinic acetylcholine receptor M1 169	Antagonist 2,778	1.5 µM [Kd]
Adrenergic receptor alpha-1 169	Antagonist 2,778	10.0 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Nausea 63	Preventing	Approved 8,429	PERPHENAZINE
Vomiting 38	Preventing	Approved 8,429	PERPHENAZINE
Schizophrenia 298	Primary	Approved 8,429	PERPHENAZINE
Anxiety 267	Primary	Approved 8,429	PERPHENAZINE AND AMITRIPTYLINE HYDROCHLORIDE
Depression 235	Primary	Approved 8,429	PERPHENAZINE AND AMITRIPTYLINE HYDROCHLORIDE

C_max

Value	Dose	Analyte	Population
509 pg/mL	4 mg 3 times / day steady-state, oral	7-HYDROXYPERPHENAZINE plasma	Homo sapiens
0.546 ng/mL	16 mg single, oral	PERPHENAZINE plasma	Homo sapiens
984 pg/mL	4 mg 3 times / day steady-state, oral	PERPHENAZINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
6.673 ng × h/mL	16 mg single, oral		PERPHENAZINE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
18.8 h	4 mg 3 times / day steady-state, oral	7-HYDROXYPERPHENAZINE plasma	Homo sapiens
9.12 h	16 mg single, oral	PERPHENAZINE plasma	Homo sapiens
12 h	4 mg 3 times / day steady-state, oral	PERPHENAZINE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
9%	unknown, unknown		PERPHENAZINE unknown	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
0.93 g single, oral Overdose	unhealthy, 42 n = 1	Disc. AE: QT interval prolonged, Hypothermia...
200 mg single, oral Overdose	unhealthy, 48 n = 1	Disc. AE: Coma, Hypothermia...
30 mg 1 times / day multiple, intramuscular (total daily dose) Recommended	unhealthy	Disc. AE: Tardive dyskinesia...
30 mg 1 times / day multiple, intramuscular (total daily dose) Recommended	unhealthy	Disc. AE: Neuroleptic malignant syndrome...
64 mg 1 times / day multiple, oral (total daily dose) Recommended	unhealthy	Disc. AE: Tardive dyskinesia...

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AEs

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AE	Significance	Dose	Population
Hypothermia	Disc. AE	0.93 g single, oral Overdose	unhealthy, 42 n = 1
Loss of consciousness	Disc. AE	0.93 g single, oral Overdose	unhealthy, 42 n = 1
PR interval prolonged	Disc. AE	0.93 g single, oral Overdose	unhealthy, 42 n = 1
QRS prolonged	Disc. AE	0.93 g single, oral Overdose	unhealthy, 42 n = 1
QT interval prolonged	Disc. AE	0.93 g single, oral Overdose	unhealthy, 42 n = 1

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	inhibitor 1,767	substrate 1,217	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 CYP1A2 1,524 CYP2C19 1,478 CYP3A 214 P-gp 1,461 UGT2B10 25 K+ channels 70 Nav1.5 97	P-gp 1,537 CYP2C19 991	MRP1 48

Drug as perpetrator

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Target	Modality	Activity
CYP2C19 1,553	inhibitor 3,277	no
CYP2C9 1,819	inhibitor 3,277	no
CYP3A 298	inhibitor 3,277	no
CYP2B6 1,001	inhibitor 3,277	yes [IC50 1.5 uM]
K+ channels 70	inhibitor 3,277	yes [IC50 38.2 uM]

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Drug as victim

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Target	Modality	Activity
CYP2C19 991	substrate 3,367	yes
CYP2D6 1,217	substrate 3,367	yes
CYP3A4 1,737	substrate 3,367	yes
P-gp 1,537	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
Nav1.5 100	inhibitor 1,626
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:8028	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:8028
ChemicalBook	CB6687009	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6687009
MolPort	MolPort-001-727-942	https://www.molport.com/shop/molecule-link/MolPort-001-727-942
ZINC	ZINC000019228902	http://zinc15.docking.org/substances/ZINC000019228902
eMolecules	593689	https://www.emolecules.com/cgi-bin/more?vid=593689

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PubMed

Show entries

Title	Date	PubMed
Drug-induced extrapyramidal symptoms: their incidence and treatment.	1967 Jan	6016862
Iatrogenic epilepsy due to antidepressant drugs.	1969 Oct 11	5823053
Increased sensitivity to neuroleptics in rats with lesions of the central nervous system.	1972	5065892
Drug-induced dystonia.	1975 May	1119613
Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes.	1984 Sep	6147851

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Patents

Sample Use Guides

In Vivo Use Guide

Moderately disturbed nonhospitalized patients with schizophrenia: 4 to 8 mg t.i.d. initially; reduce as soon as possible to minimum effective dosage. Hospitalized patients with schizophrenia: 8 to 16 mg b.i.d. to q.i.d.; avoid dosages in excess of 64 mg daily. Severe nausea and vomiting in adults: 8 to 16 mg daily in divided doses; 24 mg occasionally may be necessary; early dosage reduction is desirable.

Route of Administration: Oral

In Vitro Use Guide

Perphenazine (10-100 microM) was administered, either alone or combined with dopamine, to primary mouse neuronal or intact brain culture and to a human neuroblastoma (NB) cell line (SK-N-SH). Cell viability (measured by neutral red and alamar blue), DNA fragmentation (flow cytometry-NB) were determined. Neuroblastoma: perphenazine decreased viability by 87%.