Atomoxetine (T3D2737)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (6)XML
Targets (6)
Record Information
Version2.0
Creation Date2009-07-21 20:26:28 UTC
Update Date2014-12-24 20:25:50 UTC
Accession NumberT3D2737
Identification
Common NameAtomoxetine
ClassSmall Molecule
DescriptionAtomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt of atomoxetine. This chemical is manufactured and marketed under the brand name Strattera; by Eli Lilly and Company and as a generic Attentin by Torrent Pharmaceuticals. There is currently no generic available within the United States due to patent restrictions.
Compound Type
  • Adrenergic Uptake Inhibitor
  • Amine
  • Antidepressant
  • Antidepressive Agent
  • Central Nervous System Agent
  • Drug
  • Ether
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
(-)-Tomoxetine
Attentin
Strattera
Tomoxetin
Tomoxetina
Tomoxetine
Tomoxetinum
Chemical FormulaC17H21NO
Average Molecular Mass255.355 g/mol
Monoisotopic Mass255.162 g/mol
CAS Registry Number82248-59-7
IUPAC Namemethyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine
Traditional Nameatomoxetine
SMILES[H][C@](CCNC)(OC1=CC=CC=C1C)C1=CC=CC=C1
InChI IdentifierInChI=1S/C17H21NO/c1-14-8-6-7-11-16(14)19-17(12-13-18-2)15-9-4-3-5-10-15/h3-11,17-18H,12-13H2,1-2H3/t17-/m1/s1
InChI KeyInChIKey=VHGCDTVCOLNTBX-QGZVFWFLSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassPhenol ethers
Sub ClassNot Available
Direct ParentPhenol ethers
Alternative Parents
Substituents
  • Phenoxy compound
  • Phenol ether
  • Alkyl aryl ether
  • Toluene
  • Aralkylamine
  • Monocyclic benzene moiety
  • Secondary aliphatic amine
  • Ether
  • Secondary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Organic nitrogen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility27.8 mg/mL
LogP3.9
Predicted Properties
PropertyValueSource
Water Solubility0.0039 g/LALOGPS
logP3.95ALOGPS
logP3.81ChemAxon
logS-4.8ALOGPS
pKa (Strongest Basic)9.8ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area21.26 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity79.44 m³·mol⁻¹ChemAxon
Polarizability29.79 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0007-9510000000-b436c1286414de57d10e2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0a4i-0690000000-494128ae0f3b90b415b32017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-456e1257123470a131c22017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4i-0190000000-0f4cf059747adb026b962017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4i-0090000000-ecaeebd63dc195659e572017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-6da1a9a3edfed770c2cd2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00xs-0900000000-d71f5b857319380ce5952017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-01bc-2900000000-37eb3191934e545cc3382017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-014l-6900000000-6be893f7d4702639eac22017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4i-0190000000-c2030f3f981d83eacf572017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4i-0190000000-3c27da7fa8c958a76be12017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-133c9cb2f2383aa0fe8a2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00r5-1900000000-b68a2013855cb02e45122017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-01bd-1900000000-c4fd6863785e44cc724e2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-014l-3900000000-4529fcb6c89f3acafac92017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-06348bdc8d24fed52e752017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4i-0690000000-494128ae0f3b90b415b32017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 45V, Positivesplash10-0002-0900000000-133c9cb2f2383aa0fe8a2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0a4i-0190000000-3c27da7fa8c958a76be12021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 45V, Positivesplash10-0002-0900000000-6da1a9a3edfed770c2cd2021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a6r-0090000000-baa3d0729ad3bb59a89f2016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-054p-7690000000-47a6bba7ee3a8fb547e32016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9400000000-2bb86246ec7cd06126742016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0090000000-02a8368dee3cab1e17022016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0udi-2290000000-6d5c426420a70e542e1c2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a6r-9710000000-6adb2c5abb0cab9b62a82016-08-03View Spectrum
Toxicity Profile
Route of ExposureAtomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) have no effect on atomoxetine bioavailability. Absorption is minimally affected by food.
Mechanism of ToxicityThe precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined through in-vitro studies. Atomoxetine appears to have minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors.
MetabolismAtomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). Half Life: 5 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) alone or in combination with behavioral treatment, as an adjunct to psychological, educational, social, and other remedial measures.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsThe most commonly reported symptoms accompanying acute and chronic overdoses are somnolence, agitation, hyperactivity, abnormal behavior, and gastrointestinal symptoms.
TreatmentAn airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion. Activated charcoal may be useful in limiting absorption. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose. (10)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00289
HMDB IDHMDB14434
PubChem Compound ID54841
ChEMBL IDCHEMBL641
ChemSpider ID49516
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID127342
BioCyc IDNot Available
CTD IDNot Available
Stitch IDAtomoxetine
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkAtomoxetine
References
Synthesis Reference

Judith Aronhime, Stefano Bianchi, Eugenio Castelli, Paola Daverio, Silvia Mantovani, Adrienne Kovacsne-Mezei, “Processes for the preparation of atomoxetine hydrochloride.” U.S. Patent US20060211772, issued September 21, 2006.

MSDST3D2737.pdf
General References
  1. Spencer TJ, Faraone SV, Michelson D, Adler LA, Reimherr FW, Glatt SJ, Biederman J: Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity. J Clin Psychiatry. 2006 Mar;67(3):415-20. [16649828 ]
  2. Pilhatsch MK, Burghardt R, Wandinger KP, Bauer M, Adli M: Augmentation with atomoxetine in treatment-resistant depression with psychotic features. A case report. Pharmacopsychiatry. 2006 Mar;39(2):79-80. [16555170 ]
  3. Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH: Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005 Oct;66(10):1234-8. [16259536 ]
  4. Kratochvil CJ, Newcorn JH, Arnold LE, Duesenberg D, Emslie GJ, Quintana H, Sarkis EH, Wagner KD, Gao H, Michelson D, Biederman J: Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms. J Am Acad Child Adolesc Psychiatry. 2005 Sep;44(9):915-24. [16113620 ]
  5. McElroy SL, Guerdjikova A, Kotwal R, Welge JA, Nelson EB, Lake KA, Keck PE Jr, Hudson JI: Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry. 2007 Mar;68(3):390-8. [17388708 ]
  6. Purper-Ouakil D, Fourneret P, Wohl M, Reneric JP: [Atomoxetine: a new treatment for Attention Deficit/Hyperactivity Disorder (ADHD) in children and adolescents]. Encephale. 2005 May-Jun;31(3):337-48. [16142049 ]
  7. Montoya A, Hervas A, Cardo E, Artigas J, Mardomingo MJ, Alda JA, Gastaminza X, Garcia-Polavieja MJ, Gilaberte I, Escobar R: Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder. Curr Med Res Opin. 2009 Nov;25(11):2745-54. doi: 10.1185/03007990903316152. [19785510 ]
  8. Gaillez C, Sorbara F, Perrin E: [Atomoxetine (Strattera), an alternative in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children]. Encephale. 2007 Sep;33(4 Pt 1):621-8. [18033153 ]
  9. Drugs.com [Link]
  10. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. 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
TypeValueAssay TypeAssay Source
IC500.003 uMNot AvailableBindingDB 50366567
IC500.0031 uMNot AvailableBindingDB 50366567
IC500.005 uMNot AvailableBindingDB 50366567
IC500.0051 uMNot AvailableBindingDB 50366567
Dissociation0.00203 uMNot AvailableBindingDB 50366567
References
  1. Biederman J, Heiligenstein JH, Faries DE, Galil N, Dittmann R, Emslie GJ, Kratochvil CJ, Laws HF, Schuh KJ: Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics. 2002 Dec;110(6):e75. [12456942 ]
  2. Spencer T, Heiligenstein JH, Biederman J, Faries DE, Kratochvil CJ, Conners CK, Potter WZ: Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002 Dec;63(12):1140-7. [12523874 ]
  3. Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D: Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003 Jan 15;53(2):112-20. [12547466 ]
  4. Wernicke JF, Faries D, Girod D, Brown J, Gao H, Kelsey D, Quintana H, Lipetz R, Michelson D, Heiligenstein J: Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf. 2003;26(10):729-40. [12862507 ]
  5. Wernicke JF, Adler L, Spencer T, West SA, Allen AJ, Heiligenstein J, Milton D, Ruff D, Brown WJ, Kelsey D, Michelson D: Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: a prospective, placebo-controlled assessment. J Clin Psychopharmacol. 2004 Feb;24(1):30-5. [14709944 ]
  6. 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 ]
  7. McComas CC, Vu AT, Mahaney PE, Cohn ST, Fensome A, Marella MA, Nogle L, Trybulski EJ, Ye F, Zhang P, Alfinito P, Bray J, Johnston G, Koury E, Deecher DC: Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors. Bioorg Med Chem Lett. 2008 Sep 15;18(18):4929-31. doi: 10.1016/j.bmcl.2008.08.060. Epub 2008 Aug 22. [18771916 ]
  8. Zhang P, Terefenko EA, McComas CC, Mahaney PE, Vu A, Trybulski E, Koury E, Johnston G, Bray J, Deecher D: Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors. Bioorg Med Chem Lett. 2008 Dec 1;18(23):6067-70. doi: 10.1016/j.bmcl.2008.10.026. Epub 2008 Oct 11. [18951020 ]
  9. Vu AT, Cohn ST, Terefenko EA, Moore WJ, Zhang P, Mahaney PE, Trybulski EJ, Goljer I, Dooley R, Bray JA, Johnston GH, Leiter J, Deecher DC: 3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors. Bioorg Med Chem Lett. 2009 May 1;19(9):2464-7. doi: 10.1016/j.bmcl.2009.03.054. Epub 2009 Mar 18. [19329313 ]
  10. Fensome A, Goldberg J, McComas CC, Trybulski EJ, Woodworth RP, Deecher DC, Whiteside GT, Zhang P: Structure-activity relationships of norepinephrine reuptake inhibitors with benzothiadiazine dioxide or dihydrosulfostyril cores. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1555-8. doi: 10.1016/j.bmcl.2010.01.056. Epub 2010 Jan 20. [20153188 ]
  11. Zhang P, Terefenko EA, Bray J, Deecher D, Fensome A, Harrison J, Kim C, Koury E, Mark L, McComas CC, Mugford CA, Trybulski EJ, Vu AT, Whiteside GT, Mahaney PE: 1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors. J Med Chem. 2009 Sep 24;52(18):5703-11. doi: 10.1021/jm900888c. [19722525 ]
  12. Wu D, Pontillo J, Ching B, Hudson S, Gao Y, Fleck BA, Gogas K, Wade WS: Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI). Bioorg Med Chem Lett. 2008 Jul 15;18(14):4224-7. doi: 10.1016/j.bmcl.2008.05.057. Epub 2008 May 20. [18550369 ]
  13. Hudson S, Kiankarimi M, Eccles W, Dwight W, Mostofi YS, Genicot MJ, Fleck BA, Gogas K, Aparicio A, Wang H, Wen J, Wade WS: Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4491-4. doi: 10.1016/j.bmcl.2008.07.049. Epub 2008 Jul 17. [18672364 ]
  14. Chen C, Dyck B, Fleck BA, Foster AC, Grey J, Jovic F, Mesleh M, Phan K, Tamiya J, Vickers T, Zhang M: Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1346-9. doi: 10.1016/j.bmcl.2008.01.011. Epub 2008 Jan 9. [18207394 ]
  15. Tamiya J, Dyck B, Zhang M, Phan K, Fleck BA, Aparicio A, Jovic F, Tran JA, Vickers T, Grey J, Foster AC, Chen C: Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3328-32. doi: 10.1016/j.bmcl.2008.04.025. Epub 2008 Apr 15. [18445525 ]
  16. Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C: Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain. J Med Chem. 2008 Nov 27;51(22):7265-72. doi: 10.1021/jm8009537. [18954038 ]
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
TypeValueAssay TypeAssay Source
IC500.048 uMNot AvailableBindingDB 50366567
IC500.18 uMNot AvailableBindingDB 50366567
IC500.19 uMNot AvailableBindingDB 50366567
Dissociation0.0089 uMNot AvailableBindingDB 50366567
References
  1. 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 ]
  2. 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 ]
  3. McComas CC, Vu AT, Mahaney PE, Cohn ST, Fensome A, Marella MA, Nogle L, Trybulski EJ, Ye F, Zhang P, Alfinito P, Bray J, Johnston G, Koury E, Deecher DC: Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors. Bioorg Med Chem Lett. 2008 Sep 15;18(18):4929-31. doi: 10.1016/j.bmcl.2008.08.060. Epub 2008 Aug 22. [18771916 ]
  4. Zhang P, Terefenko EA, McComas CC, Mahaney PE, Vu A, Trybulski E, Koury E, Johnston G, Bray J, Deecher D: Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors. Bioorg Med Chem Lett. 2008 Dec 1;18(23):6067-70. doi: 10.1016/j.bmcl.2008.10.026. Epub 2008 Oct 11. [18951020 ]
  5. Vu AT, Cohn ST, Terefenko EA, Moore WJ, Zhang P, Mahaney PE, Trybulski EJ, Goljer I, Dooley R, Bray JA, Johnston GH, Leiter J, Deecher DC: 3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors. Bioorg Med Chem Lett. 2009 May 1;19(9):2464-7. doi: 10.1016/j.bmcl.2009.03.054. Epub 2009 Mar 18. [19329313 ]
  6. Wu D, Pontillo J, Ching B, Hudson S, Gao Y, Fleck BA, Gogas K, Wade WS: Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI). Bioorg Med Chem Lett. 2008 Jul 15;18(14):4224-7. doi: 10.1016/j.bmcl.2008.05.057. Epub 2008 May 20. [18550369 ]
  7. Hudson S, Kiankarimi M, Eccles W, Dwight W, Mostofi YS, Genicot MJ, Fleck BA, Gogas K, Aparicio A, Wang H, Wen J, Wade WS: Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4491-4. doi: 10.1016/j.bmcl.2008.07.049. Epub 2008 Jul 17. [18672364 ]
  8. Chen C, Dyck B, Fleck BA, Foster AC, Grey J, Jovic F, Mesleh M, Phan K, Tamiya J, Vickers T, Zhang M: Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1346-9. doi: 10.1016/j.bmcl.2008.01.011. Epub 2008 Jan 9. [18207394 ]
  9. Tamiya J, Dyck B, Zhang M, Phan K, Fleck BA, Aparicio A, Jovic F, Tran JA, Vickers T, Grey J, Foster AC, Chen C: Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3328-32. doi: 10.1016/j.bmcl.2008.04.025. Epub 2008 Apr 15. [18445525 ]
  10. Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C: Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain. J Med Chem. 2008 Nov 27;51(22):7265-72. doi: 10.1021/jm8009537. [18954038 ]
Target Details
3. 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
TypeValueAssay TypeAssay Source
IC503 uMNot AvailableBindingDB 50366567
IC503.1 uMNot AvailableBindingDB 50366567
Dissociation1.08 uMNot AvailableBindingDB 50366567
References
  1. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW: Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002 Nov;27(5):699-711. [12431845 ]
  2. 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 ]
  3. Wu D, Pontillo J, Ching B, Hudson S, Gao Y, Fleck BA, Gogas K, Wade WS: Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI). Bioorg Med Chem Lett. 2008 Jul 15;18(14):4224-7. doi: 10.1016/j.bmcl.2008.05.057. Epub 2008 May 20. [18550369 ]
  4. Hudson S, Kiankarimi M, Eccles W, Dwight W, Mostofi YS, Genicot MJ, Fleck BA, Gogas K, Aparicio A, Wang H, Wen J, Wade WS: Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4491-4. doi: 10.1016/j.bmcl.2008.07.049. Epub 2008 Jul 17. [18672364 ]
  5. Chen C, Dyck B, Fleck BA, Foster AC, Grey J, Jovic F, Mesleh M, Phan K, Tamiya J, Vickers T, Zhang M: Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1346-9. doi: 10.1016/j.bmcl.2008.01.011. Epub 2008 Jan 9. [18207394 ]
  6. Tamiya J, Dyck B, Zhang M, Phan K, Fleck BA, Aparicio A, Jovic F, Tran JA, Vickers T, Grey J, Foster AC, Chen C: Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3328-32. doi: 10.1016/j.bmcl.2008.04.025. Epub 2008 Apr 15. [18445525 ]
  7. Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C: Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain. J Med Chem. 2008 Nov 27;51(22):7265-72. doi: 10.1021/jm8009537. [18954038 ]
Target Details
4. 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
TypeValueAssay TypeAssay Source
IC502 uMNot AvailableBindingDB 50366567
References
  1. Hudson S, Kiankarimi M, Eccles W, Dwight W, Mostofi YS, Genicot MJ, Fleck BA, Gogas K, Aparicio A, Wang H, Wen J, Wade WS: Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4491-4. doi: 10.1016/j.bmcl.2008.07.049. Epub 2008 Jul 17. [18672364 ]
5. NMDA receptor (Protein Group)
General Function:
Voltage-gated cation channel activity
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity).
Included Proteins:
Q05586 , Q12879 , Q13224 , Q14957 , O15399 , Q8TCU5 , O60391
References
  1. Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, Fegert JM, Boeckers TM, Fohr KJ: Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br J Pharmacol. 2010 May;160(2):283-91. doi: 10.1111/j.1476-5381.2010.00707.x. [20423340 ]
Target Details
6. 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
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC502.1 uMNot AvailableBindingDB 50366567
References
  1. Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C: Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain. J Med Chem. 2008 Nov 27;51(22):7265-72. doi: 10.1021/jm8009537. [18954038 ]