T3DB: Nefazodone

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (14)XML

Targets (14)

Record Information

Version

2.0

Creation Date

2009-07-21 20:28:27 UTC

Update Date

2014-12-24 20:25:55 UTC

Accession Number

T3D2995

Identification

Common Name

Nefazodone

Class

Small Molecule

Description

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. [Wikipedia]

Compound Type

Amine
Analgesic
Antidepressant
Antidepressant, Second-Generation
Antidepressive Agent
Antidepressive Agent, Second-Generation
Drug
Ether
Metabolite
Organic Compound
Organochloride
Serotonin Agent
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
1-(3-(4-(m-Chlorophenyl)-1-piperazinyl)propyl)-3-ethyl-4-(2-phenoxyethyl)-delta2-1,2,4-triazolin-5-one
Dutonin
Nefazodona
Nefazodonum
Serzone

Chemical Formula

C₂₅H₃₂ClN₅O₂

Average Molecular Mass

470.007 g/mol

Monoisotopic Mass

469.224 g/mol

CAS Registry Number

83366-66-9

IUPAC Name

1-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-3-ethyl-4-(2-phenoxyethyl)-4,5-dihydro-1H-1,2,4-triazol-5-one

Traditional Name

nefazodone

SMILES

CCC1=NN(CCCN2CCN(CC2)C2=CC=CC(Cl)=C2)C(=O)N1CCOC1=CC=CC=C1

InChI Identifier

InChI=1S/C25H32ClN5O2/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

InChI Key

InChIKey=VRBKIVRKKCLPHA-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as phenylpiperazines. Phenylpiperazines are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazinanes

Sub Class

Piperazines

Direct Parent

Phenylpiperazines

Alternative Parents

Substituents

Phenylpiperazine
N-arylpiperazine
Phenol ether
Tertiary aliphatic/aromatic amine
Phenoxy compound
Dialkylarylamine
Aniline or substituted anilines
Chlorobenzene
N-alkylpiperazine
Halobenzene
Alkyl aryl ether
Monocyclic benzene moiety
Aryl halide
Aryl chloride
Benzenoid
Heteroaromatic compound
Azole
1,2,4-triazole
Tertiary aliphatic amine
Tertiary amine
Ether
Azacycle
Organooxygen compound
Organonitrogen compound
Organochloride
Organohalogen compound
Organic oxide
Organopnictogen compound
Organic oxygen compound
Hydrocarbon derivative
Organic nitrogen compound
Amine
Aromatic heteromonocyclic compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

aromatic ether (CHEBI:7494 )
N-arylpiperazine (CHEBI:7494 )
monochlorobenzenes (CHEBI:7494 )
N-alkylpiperazine (CHEBI:7494 )
triazoles (CHEBI:7494 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	83.5°C
Boiling Point	Not Available
Solubility	6.98e-02 g/L
LogP	4.7

Predicted Properties

Property	Value	Source
Water Solubility	0.07 g/L	ALOGPS
logP	3.71	ALOGPS
logP	4.65	ChemAxon
logS	-3.8	ALOGPS
pKa (Strongest Basic)	7.09	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	51.62 Å²	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	132.38 m³·mol⁻¹	ChemAxon
Polarizability	51.85 Å³	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-08fv-6496100000-3f42082c30f022624e00	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-00di-0260900000-3ebf8f0b9eda5fea1378	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-00di-3790200000-9f64b1295a633dcdd772	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-00di-0190600000-e660a26f2b5417360e81	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-00di-0152900000-340890a453c0a56c76b3	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0fbl-4695100000-93bef331c390dbfee2d6	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-01pd-7940000000-d9eeb95454a6d048ce65	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-016r-3931500000-a506620891ae02e35e82	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-002f-9730100000-83a513c505af8bed8b82	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9200000000-522fe62ba68195d5d1b2	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-00di-1200900000-c3db8beb65c2741f9ab9	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-00dr-2359600000-4969e962cd4b5264e810	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-002s-1981100000-c2114e4725584e3d862a	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0007-6805900000-806a5c4806b242b95249	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0006-9014200000-f95736b782384e65b6cf	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9000000000-37e7f69fd131b8f395dd	2021-10-11	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0uk9-9846000000-49cb6e97c09a9e806dd5	2014-09-20	View Spectrum

Toxicity Profile

Route of Exposure

Nefazodone is rapidly and completely absorbed. Its absolute bioavailability is low (about 20%).

Mechanism of Toxicity

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.

Metabolism

Hepatic. Route of Elimination: Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Half Life: 2-4 hours

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

Nefazodone (sold as Serzone, Nefadar) is a psychoactive drug and antidepressant. [wikipedia]

Minimum Risk Level

Not Available

Health Effects

Serious side effects include an allergic reaction, fainting, or painful/prolonged erection. [Wikipedia]

Symptoms

Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone.

Treatment

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known. (3)

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

7494

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Nefazodone

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Nefazodone

References

Synthesis Reference

DrugSyn.org

MSDS

T3D2995.pdf

General References

Davis R, Whittington R, Bryson HM: Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression. Drugs. 1997 Apr;53(4):608-36. [9098663 ]
Drugs.com [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. 5-hydroxytryptamine receptor 2A

General Function:: Virus receptor activity
Specific Function:: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.(Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.
Gene Name:: HTR2A
Uniprot ID:: P28223
Molecular Weight:: 52602.58 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0058 uM	Not Available	BindingDB 50069447

References

Hidalgo R, Hertzberg MA, Mellman T, Petty F, Tucker P, Weisler R, Zisook S, Chen S, Churchill E, Davidson J: Nefazodone in post-traumatic stress disorder: results from six open-label trials. Int Clin Psychopharmacol. 1999 Mar;14(2):61-8. [10220119 ]
Meyer JH, Cho R, Kennedy S, Kapur S: The effects of single dose nefazodone and paroxetine upon 5-HT2A binding potential in humans using [18F]-setoperone PET. Psychopharmacology (Berl). 1999 Jun;144(3):279-81. [10435395 ]
Horton JC, Trobe JD: Akinetopsia from nefazodone toxicity. Am J Ophthalmol. 1999 Oct;128(4):530-1. [10577608 ]
Eckler JR, Rabin RA, Winter JC: Nefazodone in the rat: mimicry and antagonism of [-]-DOM-induced stimulus control. Pharmacol Biochem Behav. 2003 May;75(2):405-10. [12873632 ]
Avila A, Cardona X, Martin-Baranera M, Maho P, Sastre F, Bello J: Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol. 2003 Oct;23(5):509-13. [14520130 ]
Seo HJ, Park EJ, Kim MJ, Kang SY, Lee SH, Kim HJ, Lee KN, Jung ME, Lee M, Kim MS, Son EJ, Park WK, Kim J, Lee J: Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter. J Med Chem. 2011 Sep 22;54(18):6305-18. doi: 10.1021/jm200682b. Epub 2011 Aug 23. [21823597 ]

Target Details

2. Sodium-dependent serotonin transporter

General Function:: Serotonin:sodium symporter activity
Specific Function:: Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.
Gene Name:: SLC6A4
Uniprot ID:: P31645
Molecular Weight:: 70324.165 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.2 uM	Not Available	BindingDB 50069447
Inhibitory	0.29 uM	Not Available	BindingDB 50069447
Inhibitory	0.459 uM	Not Available	BindingDB 50069447
Inhibitory	0.549 uM	Not Available	BindingDB 50069447
Dissociation	0.2 uM	Not Available	BindingDB 50069447

References

Owens MJ, Ieni JR, Knight DL, Winders K, Nemeroff CB: The serotonergic antidepressant nefazodone inhibits the serotonin transporter: in vivo and ex vivo studies. Life Sci. 1995;57(24):PL373-80. [7475971 ]
Narayan M, Anderson G, Cellar J, Mallison RT, Price LH, Nelson JC: Serotonin transporter-blocking properties of nefazodone assessed by measurement of platelet serotonin. J Clin Psychopharmacol. 1998 Feb;18(1):67-71. [9472845 ]
Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA: Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group. Bioorg Med Chem Lett. 1998 Mar 3;8(5):487-92. [9871604 ]
Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
Seo HJ, Park EJ, Kim MJ, Kang SY, Lee SH, Kim HJ, Lee KN, Jung ME, Lee M, Kim MS, Son EJ, Park WK, Kim J, Lee J: Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter. J Med Chem. 2011 Sep 22;54(18):6305-18. doi: 10.1021/jm200682b. Epub 2011 Aug 23. [21823597 ]
Owens MJ, Morgan WN, Plott SJ, Nemeroff CB: Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997 Dec;283(3):1305-22. [9400006 ]

Target Details

3. Sodium-dependent noradrenaline transporter

General Function:: Norepinephrine:sodium symporter activity
Specific Function:: Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:: SLC6A2
Uniprot ID:: P23975
Molecular Weight:: 69331.42 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.36 uM	Not Available	BindingDB 50069447
Inhibitory	0.618 uM	Not Available	BindingDB 50069447
Inhibitory	0.713 uM	Not Available	BindingDB 50069447
Dissociation	0.36 uM	Not Available	BindingDB 50069447

References

Owens MJ, Ieni JR, Knight DL, Winders K, Nemeroff CB: The serotonergic antidepressant nefazodone inhibits the serotonin transporter: in vivo and ex vivo studies. Life Sci. 1995;57(24):PL373-80. [7475971 ]
Owen D, Du L, Bakish D, Lapierre YD, Hrdina PD: Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression. Psychiatry Res. 1999 Jul 30;87(1):1-5. [10512149 ]
Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA: Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group. Bioorg Med Chem Lett. 1998 Mar 3;8(5):487-92. [9871604 ]
Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
Owens MJ, Morgan WN, Plott SJ, Nemeroff CB: Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997 Dec;283(3):1305-22. [9400006 ]

Target Details

4. 5-hydroxytryptamine receptor 2C

General Function:: Serotonin receptor activity
Specific Function:: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.
Gene Name:: HTR2C
Uniprot ID:: P28335
Molecular Weight:: 51820.705 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.026 uM	Not Available	BindingDB 50069447

References

Millan MJ: Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie. 2005 Sep-Oct;60(5):441-60. [16433010 ]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]
Chanrion B, Mannoury la Cour C, Gavarini S, Seimandi M, Vincent L, Pujol JF, Bockaert J, Marin P, Millan MJ: Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction. Mol Pharmacol. 2008 Mar;73(3):748-57. Epub 2007 Dec 14. [18083778 ]

Target Details

5. Alpha-1A adrenergic receptor

General Function:: Protein heterodimerization activity
Specific Function:: This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.
Gene Name:: ADRA1A
Uniprot ID:: P35348
Molecular Weight:: 51486.005 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]

Target Details

6. Alpha-2A adrenergic receptor

General Function:: Thioesterase binding
Specific Function:: Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.
Gene Name:: ADRA2A
Uniprot ID:: P08913
Molecular Weight:: 48956.275 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.084 uM	Not Available	BindingDB 50069447
Inhibitory	0.64 uM	Not Available	BindingDB 50069447

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]
Owens MJ, Morgan WN, Plott SJ, Nemeroff CB: Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997 Dec;283(3):1305-22. [9400006 ]

Target Details

7. Sodium-dependent dopamine transporter

General Function:: Monoamine transmembrane transporter activity
Specific Function:: Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:: SLC6A3
Uniprot ID:: Q01959
Molecular Weight:: 68494.255 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.36 uM	Not Available	BindingDB 50069447
Dissociation	0.36 uM	Not Available	BindingDB 50069447

References

Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA: Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group. Bioorg Med Chem Lett. 1998 Mar 3;8(5):487-92. [9871604 ]

Target Details

8. 5-hydroxytryptamine receptor 1A

General Function:: Serotonin receptor activity
Specific Function:: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli.
Gene Name:: HTR1A
Uniprot ID:: P08908
Molecular Weight:: 46106.335 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.08 uM	Not Available	BindingDB 50069447

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]

Target Details

9. Alpha-1B adrenergic receptor

General Function:: Protein heterodimerization activity
Specific Function:: This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine (PE)-stimulated ERK signaling in cardiac myocytes.
Gene Name:: ADRA1B
Uniprot ID:: P35368
Molecular Weight:: 56835.375 Da

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]

Target Details

10. Cytochrome P450 3A4

General Function:: Vitamin d3 25-hydroxylase activity
Specific Function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:: CYP3A4
Uniprot ID:: P08684
Molecular Weight:: 57342.67 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	1 uM	Not Available	BindingDB 50069447
IC50	0.015 uM	Not Available	BindingDB 50069447
IC50	1.5 uM	Not Available	BindingDB 50069447

References

Orr ST, Ripp SL, Ballard TE, Henderson JL, Scott DO, Obach RS, Sun H, Kalgutkar AS: Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks. J Med Chem. 2012 Jun 14;55(11):4896-933. doi: 10.1021/jm300065h. Epub 2012 Mar 27. [22409598 ]

Target Details

11. Histamine H1 receptor

General Function:: Histamine receptor activity
Specific Function:: In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system.
Gene Name:: HRH1
Uniprot ID:: P35367
Molecular Weight:: 55783.61 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50069447

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]

Target Details

12. Multidrug resistance protein 1

General Function:: Xenobiotic-transporting atpase activity
Specific Function:: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:: ABCB1
Uniprot ID:: P08183
Molecular Weight:: 141477.255 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	4.7 uM	Not Available	BindingDB 50069447

References

Stormer E, von Moltke LL, Perloff MD, Greenblatt DJ: P-glycoprotein interactions of nefazodone and trazodone in cell culture. J Clin Pharmacol. 2001 Jul;41(7):708-14. [11452702 ]

Target Details

13. Muscarinic acetylcholine receptor M2

General Function:: G-protein coupled acetylcholine receptor activity
Specific Function:: The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol.
Gene Name:: CHRM2
Uniprot ID:: P08172
Molecular Weight:: 51714.605 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50069447

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]

Target Details

14. Potassium voltage-gated channel subfamily H member 2

General Function:: Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:: Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:: KCNH2
Uniprot ID:: Q12809
Molecular Weight:: 126653.52 Da

References

Shin DS, Park MJ, Lee HA, Lee JY, Chung HC, Yoo DS, Chae CH, Park SJ, Kim KS, Bae MA: A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method. Toxicol Appl Pharmacol. 2014 Feb 1;274(3):361-71. doi: 10.1016/j.taap.2013.12.012. Epub 2013 Dec 26. [24374264 ]

Nefazodone (T3D2995)

Structure for T3D2995: Nefazodone

Targets

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References

References

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References

References

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References

References