NEFAZODONE HYDROCHLORIDE

First approved in 1994

Details

Stereochemistry	ACHIRAL
Molecular Formula	C25H32ClN5O2.ClH
Molecular Weight	506.468
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CCC1=NN(CCCN2CCN(CC2)C3=CC=CC(Cl)=C3)C(=O)N1CCOC4=CC=CC=C4

InChI

InChIKey=DYCKFEBIOUQECE-UHFFFAOYSA-N

InChI=1S/C25H32ClN5O2.ClH/c1-2-24-27-31(25(32)30(24)18-19-33-23-10-4-3-5-11-23)13-7-12-28-14-16-29(17-15-28)22-9-6-8-21(26)20-22;/h3-6,8-11,20H,2,7,12-19H2,1H3;1H

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB01149
Curator's Comment: Description was created based on several sources, including https://www.drugs.com/pro/nefazodone.html

Nefazodone hydrochloride (trade name Serzone) is an antidepressant drug marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries, due to the small possibility of hepatic (liver) injury, which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in 250,000 to 300,000 patient-years. On May 20, 2004, Bristol-Myers Squibb discontinued the sale of Serzone in the United States. Within the serotonergic system, nefazodone acts as an antagonist at type 2 serotonin (5-HT2) post-synaptic receptors and, like fluoxetine-type antidepressants, inhibits pre-synaptic serotonin (5-HT) reuptake. These mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally. Nefazodone also antagonizes alpha(1)-adrenergic receptors, producing sedation, muscle relaxation, and a variety of cardiovascular effects. Nefazodone's affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, and beta or alpha(2)-adrenergic receptors is not significant.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serotonin 2a (5-HT2a) receptor 237 Target ID: CHEMBL224 Sources: http://www.drugbank.ca/drugs/DB01149	Antagonist 2849	5.8 nM [Ki]
Serotonin transporter 183 Target ID: CHEMBL228 Sources: http://www.drugbank.ca/drugs/DB01149	Antagonist 2849	290.0 nM [Ki]
Adrenergic receptor alpha-1 171 Target ID: CHEMBL2094251 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9400006	Antagonist 2849	5.5 nM [Ki]
Adrenergic receptor alpha-2 114 Target ID: CHEMBL2095158 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9400006	Antagonist 2849	84.0 nM [Ki]
Serotonin 1a (5-HT1a) receptor 177 Target ID: CHEMBL214 Sources: http://www.drugbank.ca/drugs/DB01149	Antagonist 2849	52.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Depression 240 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/076037s011lbl.pdf	Primary		Approved 8583	NEFAZODONE HYDROCHLORIDE Approved Use Nefazodone hydrochloride tablets are indicated for the treatment of depression. When deciding among the alternative treatments available for this condition, the prescriber should consider the risk of hepatic failure associated with Nefazodone hydrochloride treatment. In many cases, this would lead to the conclusion that other drugs should be tried first. Launch Date 2003

C_max

Value	Dose	Analyte	Population
880 μg/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
276 μg/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
415 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
1588 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

AUC

Value	Dose	Analyte	Population
3213 μg × h/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
787 μg × h/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1220 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
6378 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

T_1/2

Value	Dose	Analyte	Population
7 h REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5.7 h REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED

Doses

Dose	Population	Adverse events
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/
430 mg 1 times / day steady, oral Highest studied dose Dose: 430 mg, 1 times / day Route: oral Route: steady Dose: 430 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10817106/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/10817106/	Other AEs: Headaches, Dry mouth... Other AEs: Headaches (53%) Dry mouth (42%) Diarrhea (42%) Sources: https://pubmed.ncbi.nlm.nih.gov/10817106/
600 mg 1 times / day steady, oral Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/	Other AEs: Somnolence... Other AEs: Somnolence (25%) Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/
600 mg 1 times / day steady, oral Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/	Other AEs: Dry mouth, Nausea... Other AEs: Dry mouth (25%) Nausea (22%) Dizziness (17%) Constipation (14%) Asthenia (11%) Light headedness (10%) Blurred vision (9%) Confusion (7%) Abnormal vision (7%) Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/
600 mg 1 times / day steady, oral Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/	Disc. AE: Nausea, Headache... AEs leading to discontinuation/dose reduction: Nausea (3.5%) Headache (2.9%) Dizziness (1.9%) Somnolence (1.5%) Insomnia (1.5%) Asthenia (1.3%) Agitation (1.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	healthy, elderly Health Status: healthy Age Group: elderly Sex: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	healthy, younger Health Status: healthy Age Group: younger Sex: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252 substrate 1946		inhibitor 2507 substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2153 P-gp 1741 BSEP 550	P-gp 2052

Drug as perpetrator

Target	Modality	Activity
CYP1A2 2333	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	no
CYP2D6 2546	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	weak
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/11452702/	yes [IC50 4.7 uM]
BSEP 554	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/16410371/	yes [IC50 9 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	yes

Drug as victim

Target	Modality	Activity	Metabolite
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/11452702/	no
CYP2D6 1388	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	yes	mCPP 2
CYP3A4 1946	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/24374264/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:7495	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:7495
ChemicalBook	CB8144863	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8144863
eMolecules	592758	https://www.emolecules.com/cgi-bin/more?vid=592758
MolPort	MolPort-003-983-466	https://www.molport.com/shop/molecule-link/MolPort-003-983-466

PubMed

Title	Date	PubMed
Algorithm for the treatment of chronic depression.	2001	11310816
Bupropion and drug-induced parkinsonism.	2001 Aug	11526815
Opposite effects of nefazodone in two human models of anxiety.	2001 Aug	11498723
A probable interaction between a very low-dose oral contraceptive and the antidepressant nefazodone: a case report.	2001 Dec	11763013
Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone.	2001 Feb	11223106
P-glycoprotein interactions of nefazodone and trazodone in cell culture.	2001 Jul	11452702
A placebo-controlled, crossover trial of granisetron in SRI-induced sexual dysfunction.	2001 Jun	11465525
Which depressed patients respond to nefazodone and when?	2001 Mar	11305700
Prevalence of sexual dysfunction among newer antidepressants.	2002 Apr	12000211
Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents.	2002 Apr	11888558
Human CYP3A4 and the metabolism of nefazodone and hydroxynefazodone by human liver microsomes and heterologously expressed enzymes.	2002 Apr	11872324
Sexual function and satisfaction in the treatment of chronic major depression with nefazodone, psychotherapy, and their combination.	2002 Aug	12197452
Nefazodone may increase anxiety in panic disorder.	2002 Feb	11799352
Evaluating changes in sexual functioning in depressed patients: sensitivity to change of the CSFQ.	2002 Mar-Apr	11894800
Antidepressant-induced sexual dysfunction.	2002 Oct	12243609

Patents

Sample Use Guides

In Vivo Use Guide

Initial dose: 200 mg orally per day in two divided doses Maintenance dose: 300 to 600 mg orally per day

Route of Administration: Oral

In Vitro Use Guide

In vitro biliary excretion of micafungin in humans and rats was reduced by 75% in the presence of the bile salt export pump (BSEP) inhibitor nefazodone (25 uM)

Name

Type

Language

NEFAZODONE HYDROCHLORIDE

Official Name

English

BMY 13754

Preferred Name

English

NEFAZODONE HYDROCHLORIDE [MI]

Common Name

English

NEFAZODONE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

NEFAZODONE HYDROCHLORIDE [USP IMPURITY]

Common Name

English

NEFAZODONE HYDROCHLORIDE [MART.]

Common Name

English

NSC-760344

Code

English

MJ 13,754-1

Code

English

NEFAZODONE HYDROCHLORIDE [USP-RS]

Common Name

English

NEFAZODONE HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

2-(3-(4-(3-CHLOROPHENYL)-1-PIPERAZINYL)PROPYL)-5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-3H-1,2,4-TRIAZOL-3-ONE MONOHYDROCHLORIDE

Systematic Name

English

BMY-13754

Code

English

NEFAZODONE HYDROCHLORIDE [USAN]

Common Name

English

Nefazodone hydrochloride [WHO-DD]

Common Name

English

NEFAZODONE HCL

Common Name

English

3H-1,2,4-TRIAZOL-3-ONE, 2-(3-(4-(3-CHLOROPHENYL)-1-PIPERAZINYL))PROPYL)-5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-, MONOHYDROCHLORIDE

Systematic Name

English

MJ-13754-1

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C265