T3DB: Sertraline

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (9)XML

Targets (9)

Record Information

Version

2.0

Creation Date

2009-07-21 20:28:22 UTC

Update Date

2014-12-24 20:25:54 UTC

Accession Number

T3D2985

Identification

Common Name

Sertraline

Class

Small Molecule

Description

Sertraline hydrochloride belongs to a class of antidepressant agents known as selective serotonin-reuptake inhibitors (SSRIs). Despite distinct structural differences between compounds in this class, SSRIs possess similar pharmacological activity. As with other antidepressant agents, several weeks of therapy may be required before a clinical effect is seen. SSRIs are potent inhibitors of neuronal serotonin reuptake. They have little to no effect on norepinephrine or dopamine reuptake and do not antagonize α- or β-adrenergic, dopamine D₂ or histamine H₁ receptors. During acute use, SSRIs block serotonin reuptake and increase serotonin stimulation of somatodendritic 5-HT_1A and terminal autoreceptors. Chronic use leads to desensitization of somatodendritic 5-HT_1A and terminal autoreceptors. The overall clinical effect of increased mood and decreased anxiety is thought to be due to adaptive changes in neuronal function that leads to enhanced serotonergic neurotransmission. Side effects include dry mouth, nausea, dizziness, drowsiness, sexual dysfunction and headache (see Toxicity section below for a more detailed listing of side effects). Compared to other agents in this class, sertraline may cause greater diarrheal and male sexual dysfunction effects. Side effects generally occur within the first two weeks of therapy and are usually less severe and frequent than those observed with tricyclic antidepressants. Sertraline may be used to treat major depressive disorder, obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD) and social anxiety disorder (social phobia).

Compound Type

Amine
Antidepressant
Antidepressive Agent
Drug
Food Toxin
Metabolite
Organic Compound
Organochloride
Selective Serotonin Reuptake Inhibitor
Serotonin Uptake Inhibitor
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
(+)-Sertraline
(1S,4S)-Sertraline
(1S-cis)-1,2,3,4-Tetrahydro-4-(3,4-dichlorophenyl)-N-methyl-1-naphthalenamine
Apo-Sertraline
cis-(+)-Sertraline
CP 51974
Lustral
Sertralina
Sertraline hydrochloride
Sertralinum
Zoloft

Chemical Formula

C₁₇H₁₇Cl₂N

Average Molecular Mass

306.230 g/mol

Monoisotopic Mass

305.074 g/mol

CAS Registry Number

79617-96-2

IUPAC Name

(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine

Traditional Name

sertraline

SMILES

[H][C@@]1(CC[C@@]([H])(C2=CC(Cl)=C(Cl)C=C2)C2=CC=CC=C12)NC

InChI Identifier

InChI=1S/C17H17Cl2N/c1-20-17-9-7-12(13-4-2-3-5-14(13)17)11-6-8-15(18)16(19)10-11/h2-6,8,10,12,17,20H,7,9H2,1H3/t12-,17-/m0/s1

InChI Key

InChIKey=VGKDLMBJGBXTGI-SJCJKPOMSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as tametralines. Tametralines are compounds containing a tametraline moiety, which consists of a tetrahydronaphthalene linked to a phenyl group to form N-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine skeleton.

Kingdom

Super Class

Class

Sub Class

Direct Parent

Alternative Parents

Substituents

Tametraline
1,2-dichlorobenzene
Chlorobenzene
Halobenzene
Aralkylamine
Aryl chloride
Aryl halide
Monocyclic benzene moiety
Secondary aliphatic amine
Secondary amine
Organohalogen compound
Hydrocarbon derivative
Organopnictogen compound
Organic nitrogen compound
Amine
Organochloride
Organonitrogen compound
Aromatic homopolycyclic compound

Molecular Framework

Aromatic homopolycyclic compounds

External Descriptors

secondary amino compound (CHEBI:9123 )
dichlorobenzene (CHEBI:9123 )
tetralins (CHEBI:9123 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Brain
Liver
Platelet

Pathways

Not Available

Applications

Biological Roles

serotonin uptake inhibitor

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	243-245°C
Boiling Point	Not Available
Solubility	3.5mg/L
LogP	5.1

Predicted Properties

Property	Value	Source
Water Solubility	0.00014 g/L	ALOGPS
logP	5.06	ALOGPS
logP	5.15	ChemAxon
logS	-6.3	ALOGPS
pKa (Strongest Basic)	9.85	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	1	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	12.03 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	85.74 m³·mol⁻¹	ChemAxon
Polarizability	32.44 Å³	ChemAxon
Number of Rings	3	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	splash10-004j-0490000000-724d07a27d5e8d538495	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 - LC-ESI-QTOF , positive	splash10-004i-0091000000-10f81c7fd0a8c096039d	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-056r-0980000000-58873180fd0c95a215b3	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0bt9-0900000000-35c397f9293e114f3234	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0a4i-0900000000-569e7b0694b3ef81cf90	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-056r-0970000000-2de49c544ebd922028dc	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-056r-0970000000-7753c869949091f5c066	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-056r-0970000000-a995c3f140efa6578777	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-0bt9-2900000000-dee4675a5062129266c9	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-0a6r-0950000000-2a9cba59b69c41b10a59	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-0a6r-0950000000-c83a31b55267aefe212a	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-0a4i-0900000000-dd599a43cebe678e826d	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 50V, Positive	splash10-0a4i-0900000000-f3cbee6abbbc3ca370b4	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-004i-0290000000-c5202d63a9c4b21b0775	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-0910000000-565998e1b2eefa1c2ccb	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-0a4i-0900000000-fef875b785017dd6bb4f	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Positive	splash10-0bt9-0900000000-1c524b8999874349f051	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-0a4i-0900000000-bf056f6f75a4ccc5d4c9	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-056r-0980000000-58873180fd0c95a215b3	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-004i-0091000000-10f81c7fd0a8c096039d	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0139000000-4f4b68d5ff5484e81ce9	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-1779000000-742a47a4d5d21cc8acb1	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-03xr-1960000000-f03bdc5054705000574c	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0udi-0009000000-d658426c80474367477a	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0udi-0029000000-68fb5194b39f7a3d992b	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0kwo-4390000000-925d4346a5a2a057e466	2016-08-03	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-00b9-2890000000-d53a90b04ec8457ad2f1	2014-09-20	View Spectrum

Toxicity Profile

Route of Exposure

The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.

Mechanism of Toxicity

The exact mechanism of action sertraline is not fully known, but the drug appears to selectively inhibit the reuptake of serotonin at the presynaptic membrane. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. It is suggested that these modifications are responsible for the antidepressant action observed during long term administration of antidepressants. It has also been hypothesized that obsessive-compulsive disorder is caused by the dysregulation of serotonin, as it is treated by sertraline, and the drug corrects this imbalance.

Metabolism

Extensively metabolized in the liver. Sertraline metabolism involves N-demethylation, N-hydroxylation, oxidative deamination, and glucuronidation of sertraline carbamic acid. Sertraline undergoes N-demethylation primarily catalyzed by cytochrome P450 (CYP) 2B6, with CYP2C19, CYP3A4 and CYP2D6 contributing to a lesser extent. Deamination occurs via CYP3A4 and CYP2C19. In vitro studies have shown that monoamine oxidase A and B may also catalyze sertraline deamination. Sertraline N-carbamoyl glucuronidation has also been observed in human liver microsomes. Route of Elimination: Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. Half Life: The elimination half-life of sertraline is approximately 25-26 hours. The elimination half-life of desmethylsertraline is approximately 62-104 hours.

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

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

Uses/Sources

For the management of major depressive disorder, posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder with or without agoraphobia, premenstrual dysphoric disorder, social phobia, premature ejaculation, and vascular headaches.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Symptoms of toxicity include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome.

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 large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for sertraline are known. (19)

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

9123

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Sertraline

PDB ID

SRE

ACToR ID

Not Available

Wikipedia Link

Sertraline

References

Synthesis Reference

George J. Quallich, Michael T. Williams, “Process for preparing sertraline intermediates.” U.S. Patent US4839104, issued February, 1977.

MSDS

T3D2985.pdf

General References

Couzin J: The brains behind blockbusters. Science. 2005 Jul 29;309(5735):728. [16051786 ]
Fabre LF, Abuzzahab FS, Amin M, Claghorn JL, Mendels J, Petrie WM, Dube S, Small JG: Sertraline safety and efficacy in major depression: a double-blind fixed-dose comparison with placebo. Biol Psychiatry. 1995 Nov 1;38(9):592-602. [8573661 ]
Kronig MH, Apter J, Asnis G, Bystritsky A, Curtis G, Ferguson J, Landbloom R, Munjack D, Riesenberg R, Robinson D, Roy-Byrne P, Phillips K, Du Pont IJ: Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder. J Clin Psychopharmacol. 1999 Apr;19(2):172-6. [10211919 ]
Brady K, Pearlstein T, Asnis GM, Baker D, Rothbaum B, Sikes CR, Farfel GM: Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA. 2000 Apr 12;283(14):1837-44. [10770145 ]
Yonkers KA, Halbreich U, Freeman E, Brown C, Endicott J, Frank E, Parry B, Pearlstein T, Severino S, Stout A, Stone A, Harrison W: Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. A randomized controlled trial. Sertraline Premenstrual Dysphoric Collaborative Study Group. JAMA. 1997 Sep 24;278(12):983-8. [9307345 ]
Shelton RC: The role of sertraline in the management of depression. Clin Ther. 1994 Sep-Oct;16(5):768-82; discussion 767. [7859236 ]
Murdoch D, McTavish D: Sertraline. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder. Drugs. 1992 Oct;44(4):604-24. [1281075 ]
Agnel M, Esnaud H, Langer SZ, Graham D: Pharmacological characterization of the cloned human 5-hydroxytryptamine transporter. Biochem Pharmacol. 1996 May 3;51(9):1145-51. [8645336 ]
Serebruany VL, Suckow RF, Cooper TB, O'Connor CM, Malinin AI, Krishnan KR, van Zyl LT, Lekht V, Glassman AH: Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. Am J Psychiatry. 2005 Jun;162(6):1165-70. [15932816 ]
Parsey RV, Kent JM, Oquendo MA, Richards MC, Pratap M, Cooper TB, Arango V, Mann JJ: Acute occupancy of brain serotonin transporter by sertraline as measured by [11C]DASB and positron emission tomography. Biol Psychiatry. 2006 May 1;59(9):821-8. Epub 2005 Oct 6. [16213473 ]
Markovitz JH, Shuster JL, Chitwood WS, May RS, Tolbert LC: Platelet activation in depression and effects of sertraline treatment: An open-label study. Am J Psychiatry. 2000 Jun;157(6):1006-8. [10831484 ]
Obach RS, Cox LM, Tremaine LM: Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 2005 Feb;33(2):262-70. Epub 2004 Nov 16. [15547048 ]
Epperson CN, Jatlow PI, Czarkowski K, Anderson GM: Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs. Pediatrics. 2003 Nov;112(5):e425. [14595087 ]
Serebruany VL, Gurbel PA, O'Connor CM: Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. Pharmacol Res. 2001 May;43(5):453-62. [11394937 ]
Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y: The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes. Br J Clin Pharmacol. 1995 Nov;40(5):481-5. [8703653 ]
Phillips OM, Wood KM, Williams DC: Kinetics of the interaction of sertraline with the human platelet plasma membrane 5-hydroxytryptamine carrier. Eur J Pharmacol. 1988 Feb 9;146(2-3):299-306. [3371401 ]
Pivac N, Muck-Seler D, Sagud M, Jakovljevic M, Mustapic M, Mihaljevic-Peles A: Long-term sertraline treatment and peripheral biochemical markers in female depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):759-65. [12921906 ]
Drugs.com [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Down-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Targets

Target Details

1. 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
IC50	0.31 uM	Not Available	BindingDB 50028094
Dissociation	0.025 uM	Not Available	BindingDB 50028094

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 ]
Ghanizadeh A: Sertraline-associated hair loss. J Drugs Dermatol. 2008 Jul;7(7):693-4. [18664165 ]
Lemke MR: [Antidepressant effects of dopamine agonists. Experimental and clinical findings]. Nervenarzt. 2007 Jan;78(1):31-8. [17187269 ]
Nemeroff CB, Owens MJ: Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis. CNS Spectr. 2004 Jun;9(6 Suppl 4):23-31. [15181382 ]
Goodnick PJ, Goldstein BJ: Selective serotonin reuptake inhibitors in affective disorders--I. Basic pharmacology. J Psychopharmacol. 1998;12(3 Suppl B):S5-20. [9808077 ]
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 ]
Middleton DS, Andrews M, Glossop P, Gymer G, Jessiman A, Johnson PS, Mackenny M, Pitcher MJ, Rooker T, Stobie A, Tang K, Morgan P: Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure-activity relationships of substituted (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1434-9. Epub 2005 Nov 28. [16314097 ]
Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA: Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. [21093273 ]

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
IC50	0.003 uM	Not Available	BindingDB 50028094
Dissociation	0.00029 uM	Not Available	BindingDB 50028094

References

Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A: Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J Neurosci. 1999 Dec 1;19(23):10494-501. [10575045 ]
Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A: Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J Neurosci. 2002 Aug 1;22(15):6766-72. [12151556 ]
Borkowska A, Pilaczynska E, Araszkiewicz A, Rybakowski J: [The effect of sertraline on cognitive functions in patients with obsessive-compulsive disorder]. Psychiatr Pol. 2002 Nov-Dec;36(6 Suppl):289-95. [12647451 ]
Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB: The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology (Berl). 2004 Aug;174(4):525-9. Epub 2003 Sep 4. [12955294 ]
Chen F, Larsen MB, Neubauer HA, Sanchez C, Plenge P, Wiborg O: Characterization of an allosteric citalopram-binding site at the serotonin transporter. J Neurochem. 2005 Jan;92(1):21-8. [15606893 ]
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 ]
Middleton DS, Andrews M, Glossop P, Gymer G, Jessiman A, Johnson PS, Mackenny M, Pitcher MJ, Rooker T, Stobie A, Tang K, Morgan P: Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure-activity relationships of substituted (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1434-9. Epub 2005 Nov 28. [16314097 ]
Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA: Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. [21093273 ]

Target Details

3. 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

References

David DJ, Bourin M, Hascoet M, Colombel MC, Baker GB, Jolliet P: Comparison of antidepressant activity in 4- and 40-week-old male mice in the forced swimming test: involvement of 5-HT1A and 5-HT1B receptors in old mice. Psychopharmacology (Berl). 2001 Feb;153(4):443-9. [11243491 ]
Fornal CA, Metzler CW, Mirescu C, Stein SK, Jacobs BL: Effects of standardized extracts of St. John's wort on the single-unit activity of serotonergic dorsal Raphe neurons in awake cats: comparisons with fluoxetine and sertraline. Neuropsychopharmacology. 2001 Dec;25(6):858-70. [11750179 ]
Rossi DV, Valdez M, Gould GG, Hensler JG: Chronic administration of venlafaxine fails to attenuate 5-HT1A receptor function at the level of receptor-G protein interaction. Int J Neuropsychopharmacol. 2006 Aug;9(4):393-406. Epub 2005 Jul 22. [16035959 ]
Rogoz Z, Skuza G: Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats. Pharmacol Rep. 2006 Jul-Aug;58(4):493-500. [16963794 ]
Darmani NA, Reeves SL: The stimulatory and inhibitory components of cocaine's actions on the 5-HTP-induced 5-HT2A receptor response. Pharmacol Biochem Behav. 1996 Nov;55(3):387-96. [8951980 ]

Target Details

4. 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

References

Rasmussen BB, Brosen K: Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors? Ther Drug Monit. 2000 Apr;22(2):143-54. [10774624 ]
Rojdmark S, von Bahr C: [Metabolic interaction between psychopharmaceuticals. Probable cause of exacerbation of hypothyroidism according to a case report]. Lakartidningen. 2002 Jun 20;99(25):2854-6. [12143142 ]
DeVane CL, Donovan JL, Liston HL, Markowitz JS, Cheng KT, Risch SC, Willard L: Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. J Clin Psychopharmacol. 2004 Feb;24(1):4-10. [14709940 ]
Obach RS, Cox LM, Tremaine LM: Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 2005 Feb;33(2):262-70. Epub 2004 Nov 16. [15547048 ]
Alderman J: Coadministration of sertraline with cisapride or pimozide: an open-label, nonrandomized examination of pharmacokinetics and corrected QT intervals in healthy adult volunteers. Clin Ther. 2005 Jul;27(7):1050-63. [16154484 ]

Target Details

5. 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
IC50	0.825 uM	Not Available	BindingDB 50028094
Dissociation	0.42 uM	Not Available	BindingDB 50028094

References

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 ]
Middleton DS, Andrews M, Glossop P, Gymer G, Jessiman A, Johnson PS, Mackenny M, Pitcher MJ, Rooker T, Stobie A, Tang K, Morgan P: Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure-activity relationships of substituted (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1434-9. Epub 2005 Nov 28. [16314097 ]
Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA: Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. [21093273 ]

Target Details

6. Cytochrome P450 2C19

General Function:: Steroid hydroxylase activity
Specific Function:: Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:: CYP2C19
Uniprot ID:: P33261
Molecular Weight:: 55930.545 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	0.31 uM	Not Available	BindingDB 50028094

References

Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA: Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. [21093273 ]

Target Details

7. Cytochrome P450 2C9

General Function:: Steroid 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Gene Name:: CYP2C9
Uniprot ID:: P11712
Molecular Weight:: 55627.365 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>10 uM	Not Available	BindingDB 50028094

References

Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA: Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. [21093273 ]

Target Details

8. Cytochrome P450 2D6

General Function:: Steroid hydroxylase activity
Specific Function:: Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:: CYP2D6
Uniprot ID:: P10635
Molecular Weight:: 55768.94 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	1.4 uM	Not Available	BindingDB 50028094

References

Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA: Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. [21093273 ]

Target Details

9. 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
IC50	0.8 uM	Not Available	BindingDB 50028094

References

Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA: Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors. Bioorg Med Chem. 2011 Jan 1;19(1):663-76. doi: 10.1016/j.bmc.2010.10.034. Epub 2010 Oct 21. [21093273 ]

Sertraline (T3D2985)

Structure for T3D2985: Sertraline

Targets

Binding/Activity Constants

References

Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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