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Record Information
Version2.0
Creation Date2009-07-21 20:26:59 UTC
Update Date2014-12-24 20:25:51 UTC
Accession NumberT3D2802
Identification
Common NameFluoxetine
ClassSmall Molecule
DescriptionFluoxetine hydrochloride is the first agent of the class of antidepressants known as selective serotonin-reuptake inhibitors (SSRIs). Fluoxetine is a racemic mixture of the R- and S- enantiomers and are of equivalent pharmacologic activity. 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-HT1A and terminal autoreceptors. Chronic use leads to desensitization of somatodendritic 5-HT1A 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. Side effects generally occur within the first two weeks of therapy and are usually less severe and frequent than those observed with tricyclic antidepressants. Fluoxetine may be used to treat major depressive disorder (MDD), moderate to severe bulimia nervosa, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), panic disorder with or without agoraphobia, and in combination with olanzapine for treatment-resistant or bipolar I depression. Fluoxetine is the most anorexic and stimulating SSRI.
Compound Type
  • Amine
  • Antidepressant, Second-Generation
  • Antidepressive Agent, Second-Generation
  • Drug
  • Ether
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Selective Serotonin Reuptake Inhibitor
  • Serotonin Agent
  • Serotonin Uptake Inhibitor
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(+-)-N-Methyl-3-phenyl-3-((alpha,alpha,alpha-trifluoro-P-tolyl)oxy)propylamine
(+-)-N-Methyl-gamma-(4-(trifluoromethyl)phenoxy)benzenepropanamine
Adofen
Animex-On
Fluoxeren
Fluoxetin
Fluoxetina
Fluoxétine
Fluoxetinum
Fontex
Ladose
Prozac
Sarafem
Chemical FormulaC17H18F3NO
Average Molecular Mass309.326 g/mol
Monoisotopic Mass309.134 g/mol
CAS Registry Number54910-89-3
IUPAC Namemethyl({3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl})amine
Traditional Namefluoxetine
SMILESCNCCC(OC1=CC=C(C=C1)C(F)(F)F)C1=CC=CC=C1
InChI IdentifierInChI=1/C17H18F3NO/c1-21-12-11-16(13-5-3-2-4-6-13)22-15-9-7-14(8-10-15)17(18,19)20/h2-10,16,21H,11-12H2,1H3
InChI KeyInChIKey=RTHCYVBBDHJXIQ-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as trifluoromethylbenzenes. These are organofluorine compounds that contain a benzene ring substituted with one or more trifluoromethyl groups.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassTrifluoromethylbenzenes
Direct ParentTrifluoromethylbenzenes
Alternative Parents
Substituents
  • Trifluoromethylbenzene
  • Phenoxy compound
  • Phenol ether
  • Alkyl aryl ether
  • Aralkylamine
  • Secondary aliphatic amine
  • Ether
  • Secondary amine
  • Organic oxygen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Alkyl fluoride
  • Organic nitrogen compound
  • Amine
  • Alkyl halide
  • 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 Point179-182°C
Boiling PointNot Available
Solubility50 mg/mL at 25°C
LogP4.05
Predicted Properties
PropertyValueSource
Water Solubility0.0017 g/LALOGPS
logP4.09ALOGPS
logP4.17ChemAxon
logS-5.3ALOGPS
pKa (Strongest Basic)9.8ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area21.26 ŲChemAxon
Rotatable Bond Count7ChemAxon
Refractivity80.37 m³·mol⁻¹ChemAxon
Polarizability30.33 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0006-9530000000-45c870b2463186b9230cJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-01t9-0592000000-92a48c620c961fdb430fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-03di-0009000000-ed61090013f0dc5f5c5aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-014i-0190000000-e9bcd2accdf5b7e40a88JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-014i-0590000000-04b1d4265cb156217f40JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-014i-0790000000-5c42b9a9a2cd0c4114aaJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0gb9-0960000000-88822d2fb3e7c0cdc0b3JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-6b560941c92823b7901cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-0109000000-1531c1e1630dcb42b497JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-9000000000-53199cfe3b343ae81afdJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-0109000000-0e790a7e6032e51bfeb3JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00kf-9800000000-64d39c4a4fcc7f8b6f47JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00kf-9700000000-e516356ce3eca65bece8JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0002-0900000000-6b560941c92823b7901cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0zgi-1390000000-84c6bc70aefcd3758f31JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0f7o-6940000000-a424e26ecc7465229968JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4m-0390000000-9b7253cd5718aa434e46JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4m-0290000000-d88f8004205c7223aa9fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-01t9-0592000000-92a48c620c961fdb430fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03di-0409000000-03f5678c6178e634f254JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03fr-1179000000-9f0773309b13bac8c304JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0h03-5292000000-1e7d8430611731d4e4a8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9830000000-b2a37ff34ba2d3974989JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-1009000000-113c9621ae90d769ee33JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-3469000000-4480faded690242a155cJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-03di-2910000000-2c7cf659d217661ff897JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-0006-9200000000-dcf68dbfd090c7fdfe11JSpectraViewer | MoNA
Toxicity Profile
Route of ExposureWell absorbed from the GI tract following oral administration. Oral bioavailability is estimated to be at least 60-80%. Peak plasma concentrations occur within 6-8 hours following a single oral administration of a 40 mg dose. The oral solution and delayed-release capsule are bioequivalent. Food does not affect the systemic bioavailability of fluoxetine but it delays the absorption by 1-2 hours (not clinically significant). Prozac Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations.
Mechanism of ToxicityFluoxetine is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
MetabolismLimited data from animal studies suggest that fluoxetine may undergo first-pass metabolism may occur via the liver and/or lungs. Fluoxetine appears to be extensively metabolized, likely in the liver, to norfluoxetine and other metabolites. Norfluoxetine, the principal active metabolite, is formed via N-demethylation of fluoxetine. Norfluoxetine appears to be comparable pharmacologic potency as fluoxetine. Fluoxetine and norfluoxetine both undergo phase II glucuronidation reactions in the liver. It is also thought that fluoxetine and norfluoxetine undergo O-dealkylation to form p-trifluoromethylphenol, which is then subsequently metabolized to hippuric acid. Route of Elimination: The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. The S-enantiomer is eliminated more slowly and is the predominant enantiomer present at steady state. Half Life: 1-3 days [acute administration]; 4-6 days [chronic administration]; 4-16 days [norfluoxetine, acute and chronic administration].
Toxicity Values LD50=284mg/kg (orally in mice).
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesLabeled indication include: major depressive disorder (MDD), moderate to severe bulimia nervosa, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), panic disorder with or without agoraphobia, and combination treatment with olanzapine for treatment-resistant or bipolar I depression. Unlabeled indications include: selective mutism, mild dementia-associated agitation in nonpsychotic patients, post-traumatic stress disorder (PTSD), social anxiety disorder, chronic neuropathic pain, fibromyalgia, and Raynaud's phenomenon.
Minimum Risk LevelNot Available
Health EffectsAcute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
SymptomsSymptoms of overdose include agitation, restlessness, hypomania, and other signs of CNS excitation. The most frequent side effects include: nervous system effects such as anxiety, nervousness, insomnia, drowsiness, fatigue or asthenia, tremor, and dizziness or lightheadedness; GI effects such as anorexia, nausea, and diarrhea; vasodilation; dry mouth; abnormal vision; decreased libido; abnormal ejaculation; rash; and sweating. Withdrawal symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory changes and hyperactivity.
TreatmentIf the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00472
HMDB IDHMDB14615
PubChem Compound ID3386
ChEMBL IDCHEMBL41
ChemSpider ID3269
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID5118
BioCyc IDNot Available
CTD IDNot Available
Stitch IDFluoxetine
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkFluoxetine
References
Synthesis Reference

Eduard Schwartz, Joseph Kaspi, Zinovi Itov, Gidon Pilarski, “Production of fluoxetine and new intermediates.” U.S. Patent US5225585, issued October, 1990.

MSDSLink
General References
  1. Wong DT, Bymaster FP, Engleman EA: Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication. Life Sci. 1995;57(5):411-41. [7623609 ]
  2. Wong DT, Horng JS, Bymaster FP, Hauser KL, Molloy BB: A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sci. 1974 Aug 1;15(3):471-9. [4549929 ]
  3. Carlsson A, Wong DT: Correction: a note on the discovery of selective serotonin reuptake inhibitors. Life Sci. 1997;61(12):1203. [9315511 ]
  4. Gerber PE, Lynd LD: Selective serotonin-reuptake inhibitor-induced movement disorders. Ann Pharmacother. 1998 Jun;32(6):692-8. [9640489 ]
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  6. Drugs.com [Link]
  7. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

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
Inhibitory0.00072 uMNot AvailableBindingDB 30130
Inhibitory0.00081 uMNot AvailableBindingDB 30130
Inhibitory0.0009 uMNot AvailableBindingDB 30130
Inhibitory0.0011 uMNot AvailableBindingDB 30130
Inhibitory0.0014 uMNot AvailableBindingDB 81875
Inhibitory0.002 uMNot AvailableBindingDB 30130
Inhibitory0.0022 uMNot AvailableBindingDB 30130
Inhibitory0.0035 uMNot AvailableBindingDB 30130
Inhibitory0.0057 uMNot AvailableBindingDB 30130
Inhibitory0.007 uMNot AvailableBindingDB 30130
Inhibitory0.0103 uMNot AvailableBindingDB 30130
Inhibitory0.013 uMNot AvailableBindingDB 81875
Inhibitory0.02 uMNot AvailableBindingDB 30130
Inhibitory0.048 uMNot AvailableBindingDB 30130
IC500.0025 uMNot AvailableBindingDB 30130
IC500.0031 uMNot AvailableBindingDB 30130
IC500.0052 uMNot AvailableBindingDB 30130
IC500.0073 uMNot AvailableBindingDB 30130
IC500.0094 uMNot AvailableBindingDB 30130
IC500.01 uMNot AvailableBindingDB 30130
IC500.016 uMNot AvailableBindingDB 30130
IC500.0324 uMNot AvailableBindingDB 30130
IC500.0394 uMNot AvailableBindingDB 30130
IC500.047 uMNot AvailableBindingDB 30130
IC500.18 uMNot AvailableBindingDB 30130
Dissociation0.00081 uMNot AvailableBindingDB 30130
References
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  19. O'Neill DJ, Adedoyin A, Alfinito PD, Bray JA, Cosmi S, Deecher DC, Fensome A, Harrison J, Leventhal L, Mann C, McComas CC, Sullivan NR, Spangler TB, Uveges AJ, Trybulski EJ, Whiteside GT, Zhang P: Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231). J Med Chem. 2010 Jun 10;53(11):4511-21. doi: 10.1021/jm100053t. [20462211 ]
  20. O'Neill DJ, Adedoyin A, Bray JA, Deecher DC, Fensome A, Goldberg JA, Harrison J, Leventhal L, Mann C, Mark L, Nogle L, Sullivan NR, Spangler TB, Terefenko EA, Trybulski EJ, Uveges AJ, Vu A, Whiteside GT, Zhang P: Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152). J Med Chem. 2011 Oct 13;54(19):6824-31. doi: 10.1021/jm200733r. Epub 2011 Sep 14. [21916421 ]
  21. 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 ]
  22. 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 ]
  23. Jonathan Fray M, Bish G, Brown AD, Fish PV, Stobie A, Wakenhut F, Whitlock GA: N-(1,2-diphenylethyl)piperazines: a new class of dual serotonin/noradrenaline reuptake inhibitor. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4345-8. Epub 2006 Jun 5. [16750359 ]
  24. Fray MJ, Bish G, Fish PV, Stobie A, Wakenhut F, Whitlock GA: Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4349-53. Epub 2006 Jun 5. [16750363 ]
  25. Mewshaw RE, Zhou D, Zhou P, Shi X, Hornby G, Spangler T, Scerni R, Smith D, Schechter LE, Andree TH: Studies toward the discovery of the next generation of antidepressants. 3. Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines. J Med Chem. 2004 Jul 15;47(15):3823-42. [15239661 ]
  26. Hatzenbuhler NT, Evrard DA, Harrison BL, Huryn D, Inghrim J, Kraml C, Mattes JF, Mewshaw RE, Zhou D, Hornby G, Lin Q, Smith DL, Sullivan KM, Schechter LE, Beyer CE, Andree TH: Synthesis and biological evaluation of novel compounds within a class of 3-aminochroman derivatives with dual 5-HT1A receptor and serotonin transporter affinity. J Med Chem. 2006 Jul 27;49(15):4785-9. [16854086 ]
  27. Hatzenbuhler NT, Baudy R, Evrard DA, Failli A, Harrison BL, Lenicek S, Mewshaw RE, Saab A, Shah U, Sze J, Zhang M, Zhou D, Chlenov M, Kagan M, Golembieski J, Hornby G, Lai M, Smith DL, Sullivan KM, Schechter LE, Andree TH: Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2. J Med Chem. 2008 Nov 13;51(21):6980-7004. doi: 10.1021/jm8007097. Epub 2008 Oct 4. [18834188 ]
  28. 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 ]
  29. Hudson S, Kiankarimi M, Eccles W, Mostofi YS, Genicot MJ, Dwight W, Fleck BA, Gogas K, Wade WS: Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with a heterocyclic ring constraint. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4495-8. doi: 10.1016/j.bmcl.2008.07.050. Epub 2008 Jul 17. [18667309 ]
  30. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C: Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008 Feb 14;51(3):347-72. doi: 10.1021/jm7009364. Epub 2008 Jan 9. [18181565 ]
  31. Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ: Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors. J Med Chem. 2005 Sep 22;48(19):6023-34. [16162005 ]
  32. 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 ]
  33. 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 ]
  34. Owens JM, Knight DL, Nemeroff CB: [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]. Encephale. 2002 Jul-Aug;28(4):350-5. [12232544 ]
  35. Cashman JR, Voelker T, Zhang HT, O'Donnell JM: Dual inhibitors of phosphodiesterase-4 and serotonin reuptake. J Med Chem. 2009 Mar 26;52(6):1530-9. doi: 10.1021/jm8010993. [19256502 ]
  36. Keith JM, Gomez LA, Letavic MA, Ly KS, Jablonowski JA, Seierstad M, Barbier AJ, Wilson SJ, Boggs JD, Fraser IC, Mazur C, Lovenberg TW, Carruthers NI: Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore. Bioorg Med Chem Lett. 2007 Feb 1;17(3):702-6. Epub 2006 Nov 2. [17107798 ]
  37. Letavic MA, Keith JM, Jablonowski JA, Stocking EM, Gomez LA, Ly KS, Miller JM, Barbier AJ, Bonaventure P, Boggs JD, Wilson SJ, Miller KL, Lord B, McAllister HM, Tognarelli DJ, Wu J, Abad MC, Schubert C, Lovenberg TW, Carruthers NI: Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors. Bioorg Med Chem Lett. 2007 Feb 15;17(4):1047-51. Epub 2006 Nov 16. [17127059 ]
  38. Letavic MA, Keith JM, Ly KS, Barbier AJ, Boggs JD, Wilson SJ, Lord B, Lovenberg TW, Carruthers NI: Novel naphthyridines are histamine H3 antagonists and serotonin reuptake transporter inhibitors. Bioorg Med Chem Lett. 2007 May 1;17(9):2566-9. Epub 2007 Feb 4. [17307358 ]
  39. Letavic MA, Stocking EM, Barbier AJ, Bonaventure P, Boggs JD, Lord B, Miller KL, Wilson SJ, Carruthers NI: Benzylamine histamine H(3) antagonists and serotonin reuptake inhibitors. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4799-803. Epub 2007 Jun 26. [17616397 ]
  40. Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK: 2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors. J Med Chem. 2000 Mar 9;43(5):1011-8. [10715164 ]
  41. 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 ]
  42. Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH: Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther. 2006 Aug;318(2):657-65. Epub 2006 May 4. [16675639 ]
  43. Morphy R, Rankovic Z: Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43. [16220969 ]
  44. Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, Zou MF, Newman AH, Blakely RD: Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants. J Biol Chem. 2006 Jan 27;281(4):2012-23. Epub 2005 Nov 3. [16272152 ]
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
Inhibitory0.686 uMNot AvailableBindingDB 81875
Inhibitory0.777 uMNot AvailableBindingDB 30130
Inhibitory1.022 uMNot AvailableBindingDB 30130
Inhibitory1.56 uMNot AvailableBindingDB 30130
Inhibitory2 uMNot AvailableBindingDB 30130
Inhibitory2.186 uMNot AvailableBindingDB 30130
Inhibitory0.24 uMNot AvailableBindingDB 30130
Inhibitory0.41 uMNot AvailableBindingDB 81875
Inhibitory0.44 uMNot AvailableBindingDB 30130
Inhibitory0.574 uMNot AvailableBindingDB 30130
Inhibitory0.599 uMNot AvailableBindingDB 30130
IC500.563 uMNot AvailableBindingDB 30130
IC501.02 uMNot AvailableBindingDB 30130
IC502 uMNot AvailableBindingDB 30130
IC505.2 uMNot AvailableBindingDB 30130
Dissociation0.24 uMNot AvailableBindingDB 30130
References
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. Cashman JR, Voelker T, Johnson R, Janowsky A: Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression. Bioorg Med Chem. 2009 Jan 1;17(1):337-43. doi: 10.1016/j.bmc.2008.10.065. Epub 2008 Nov 5. [19014888 ]
  5. 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 ]
  6. Hudson S, Kiankarimi M, Eccles W, Mostofi YS, Genicot MJ, Dwight W, Fleck BA, Gogas K, Wade WS: Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with a heterocyclic ring constraint. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4495-8. doi: 10.1016/j.bmcl.2008.07.050. Epub 2008 Jul 17. [18667309 ]
  7. Jonathan Fray M, Bish G, Brown AD, Fish PV, Stobie A, Wakenhut F, Whitlock GA: N-(1,2-diphenylethyl)piperazines: a new class of dual serotonin/noradrenaline reuptake inhibitor. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4345-8. Epub 2006 Jun 5. [16750359 ]
  8. Fray MJ, Bish G, Fish PV, Stobie A, Wakenhut F, Whitlock GA: Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4349-53. Epub 2006 Jun 5. [16750363 ]
  9. 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 ]
  10. Owens JM, Knight DL, Nemeroff CB: [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]. Encephale. 2002 Jul-Aug;28(4):350-5. [12232544 ]
  11. Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ: Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors. J Med Chem. 2005 Sep 22;48(19):6023-34. [16162005 ]
  12. 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 ]
  13. 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 ]
  14. Cashman JR, Voelker T, Zhang HT, O'Donnell JM: Dual inhibitors of phosphodiesterase-4 and serotonin reuptake. J Med Chem. 2009 Mar 26;52(6):1530-9. doi: 10.1021/jm8010993. [19256502 ]
  15. Morphy R, Rankovic Z: Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43. [16220969 ]
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
Inhibitory1.9 uMNot AvailableBindingDB 30130
Inhibitory3.097 uMNot AvailableBindingDB 81875
Inhibitory3.6 uMNot AvailableBindingDB 30130
Inhibitory3.764 uMNot AvailableBindingDB 30130
Inhibitory4.752 uMNot AvailableBindingDB 30130
Inhibitory4.974 uMNot AvailableBindingDB 81875
Inhibitory5.96 uMNot AvailableBindingDB 30130
Inhibitory6 uMNot AvailableBindingDB 30130
Inhibitory6.67 uMNot AvailableBindingDB 30130
IC504.4 uMNot AvailableBindingDB 30130
IC506 uMNot AvailableBindingDB 30130
IC5019.5 uMNot AvailableBindingDB 30130
Dissociation3.6 uMNot AvailableBindingDB 30130
References
  1. 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 ]
  2. Jonathan Fray M, Bish G, Brown AD, Fish PV, Stobie A, Wakenhut F, Whitlock GA: N-(1,2-diphenylethyl)piperazines: a new class of dual serotonin/noradrenaline reuptake inhibitor. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4345-8. Epub 2006 Jun 5. [16750359 ]
  3. Fray MJ, Bish G, Fish PV, Stobie A, Wakenhut F, Whitlock GA: Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4349-53. Epub 2006 Jun 5. [16750363 ]
  4. 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 ]
  5. Hudson S, Kiankarimi M, Eccles W, Mostofi YS, Genicot MJ, Dwight W, Fleck BA, Gogas K, Wade WS: Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with a heterocyclic ring constraint. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4495-8. doi: 10.1016/j.bmcl.2008.07.050. Epub 2008 Jul 17. [18667309 ]
  6. Cashman JR, Voelker T, Johnson R, Janowsky A: Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression. Bioorg Med Chem. 2009 Jan 1;17(1):337-43. doi: 10.1016/j.bmc.2008.10.065. Epub 2008 Nov 5. [19014888 ]
  7. Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ: Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors. J Med Chem. 2005 Sep 22;48(19):6023-34. [16162005 ]
  8. Owens JM, Knight DL, Nemeroff CB: [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]. Encephale. 2002 Jul-Aug;28(4):350-5. [12232544 ]
  9. 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 ]
  10. 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 ]
  11. Morphy R, Rankovic Z: Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43. [16220969 ]
  12. Cashman JR, Voelker T, Zhang HT, O'Donnell JM: Dual inhibitors of phosphodiesterase-4 and serotonin reuptake. J Med Chem. 2009 Mar 26;52(6):1530-9. doi: 10.1021/jm8010993. [19256502 ]
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
IC501.51356 uMNot AvailableBindingDB 30130
IC501.514 uMNot AvailableBindingDB 30130
IC503.1 uMNot AvailableBindingDB 30130
References
  1. Tobita M, Nishikawa T, Nagashima R: A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors. Bioorg Med Chem Lett. 2005 Jun 2;15(11):2886-90. [15911273 ]
  2. Jia L, Sun H: Support vector machines classification of hERG liabilities based on atom types. Bioorg Med Chem. 2008 Jun 1;16(11):6252-60. doi: 10.1016/j.bmc.2008.04.028. Epub 2008 Apr 16. [18448342 ]
  3. Keseru GM: Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods. Bioorg Med Chem Lett. 2003 Aug 18;13(16):2773-5. [12873512 ]
  4. Kang SY, Park EJ, Park WK, Kim HJ, Choi G, Jung ME, Seo HJ, Kim MJ, Pae AN, Kim J, Lee J: Further optimization of novel pyrrole 3-carboxamides for targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant. Bioorg Med Chem. 2010 Aug 15;18(16):6156-69. doi: 10.1016/j.bmc.2010.06.037. Epub 2010 Jun 25. [20637635 ]
  5. Chiu PJ, Marcoe KF, Bounds SE, Lin CH, Feng JJ, Lin A, Cheng FC, Crumb WJ, Mitchell R: Validation of a [3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels. J Pharmacol Sci. 2004 Jul;95(3):311-9. [15272206 ]
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
TypeValueAssay TypeAssay Source
Inhibitory0.1122 uMNot AvailableBindingDB 30130
Inhibitory0.28 uMNot AvailableBindingDB 30130
Inhibitory0.39811 uMNot AvailableBindingDB 30130
References
  1. Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM: RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology. 1997 Apr-May;36(4-5):621-9. [9225287 ]
  2. 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 ]
  3. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M: Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004 Aug;370(2):114-23. Epub 2004 Jul 30. [15322733 ]
  4. 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 ]
General Function:
Histamine receptor activity
Specific Function:
The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization.
Gene Name:
HRH3
Uniprot ID:
Q9Y5N1
Molecular Weight:
48670.81 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory7.3 uMNot AvailableBindingDB 30130
References
  1. Keith JM, Gomez LA, Letavic MA, Ly KS, Jablonowski JA, Seierstad M, Barbier AJ, Wilson SJ, Boggs JD, Fraser IC, Mazur C, Lovenberg TW, Carruthers NI: Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore. Bioorg Med Chem Lett. 2007 Feb 1;17(3):702-6. Epub 2006 Nov 2. [17107798 ]
  2. Letavic MA, Keith JM, Jablonowski JA, Stocking EM, Gomez LA, Ly KS, Miller JM, Barbier AJ, Bonaventure P, Boggs JD, Wilson SJ, Miller KL, Lord B, McAllister HM, Tognarelli DJ, Wu J, Abad MC, Schubert C, Lovenberg TW, Carruthers NI: Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors. Bioorg Med Chem Lett. 2007 Feb 15;17(4):1047-51. Epub 2006 Nov 16. [17127059 ]
  3. Letavic MA, Keith JM, Ly KS, Barbier AJ, Boggs JD, Wilson SJ, Lord B, Lovenberg TW, Carruthers NI: Novel naphthyridines are histamine H3 antagonists and serotonin reuptake transporter inhibitors. Bioorg Med Chem Lett. 2007 May 1;17(9):2566-9. Epub 2007 Feb 4. [17307358 ]
  4. Letavic MA, Stocking EM, Barbier AJ, Bonaventure P, Boggs JD, Lord B, Miller KL, Wilson SJ, Carruthers NI: Benzylamine histamine H(3) antagonists and serotonin reuptake inhibitors. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4799-803. Epub 2007 Jun 26. [17616397 ]
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives 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. 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. Plays a role in the regulation of dopamine and 5-hydroxytryptamine release, 5-hydroxytryptamine uptake and in the regulation of extracellular dopamine and 5-hydroxytryptamine levels, and thereby affects neural activity. May play a role in the perception of pain. Plays a role in the regulation of behavior, including impulsive behavior. Required for normal proliferation of embryonic cardiac myocytes and normal heart development. Protects cardiomyocytes against apoptosis. Plays a role in the adaptation of pulmonary arteries to chronic hypoxia. Plays a role in vasoconstriction. Required for normal osteoblast function and proliferation, and for maintaining normal bone density. Required for normal proliferation of the interstitial cells of Cajal in the intestine.
Gene Name:
HTR2B
Uniprot ID:
P41595
Molecular Weight:
54297.41 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory5.03 uMNot AvailableBindingDB 30130
Inhibitory>10 uMNot AvailableBindingDB 30130
References
  1. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL: Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000 Dec 5;102(23):2836-41. [11104741 ]
  2. Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM: RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology. 1997 Apr-May;36(4-5):621-9. [9225287 ]
  3. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M: Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004 Aug;370(2):114-23. Epub 2004 Jul 30. [15322733 ]
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
TypeValueAssay TypeAssay Source
Inhibitory0.14791 uMNot AvailableBindingDB 30130
Inhibitory0.24547 uMNot AvailableBindingDB 30130
References
  1. Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM: RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology. 1997 Apr-May;36(4-5):621-9. [9225287 ]
  2. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M: Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004 Aug;370(2):114-23. Epub 2004 Jul 30. [15322733 ]
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
TypeValueAssay TypeAssay Source
Inhibitory3.09 uMNot AvailableBindingDB 30130
Inhibitory>10 uMNot AvailableBindingDB 30130
References
  1. 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 ]
  2. 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 ]
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
TypeValueAssay TypeAssay Source
Inhibitory1.1 uMNot AvailableBindingDB 30130
Inhibitory5.4 uMNot AvailableBindingDB 30130
References
  1. Kanba S, Richelson E: Histamine H1 receptors in human brain labelled with [3H]doxepin. Brain Res. 1984 Jun 18;304(1):1-7. [6146381 ]
  2. 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 ]
General Function:
Phosphatidylinositol phospholipase c 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 Pi turnover.
Gene Name:
CHRM1
Uniprot ID:
P11229
Molecular Weight:
51420.375 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.702 uMNot AvailableBindingDB 30130
Inhibitory0.998 uMNot AvailableBindingDB 81875
Inhibitory1.03 uMNot AvailableBindingDB 30130
References
  1. Owens JM, Knight DL, Nemeroff CB: [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]. Encephale. 2002 Jul-Aug;28(4):350-5. [12232544 ]
  2. Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]
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
TypeValueAssay TypeAssay Source
Inhibitory0.59 uMNot AvailableBindingDB 30130
Inhibitory2.7 uMNot AvailableBindingDB 30130
References
  1. 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 ]
  2. Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]
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
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 30130
References
  1. 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 ]
General Function:
Serine hydrolase activity
Specific Function:
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name:
ACHE
Uniprot ID:
P22303
Molecular Weight:
67795.525 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>10 uMNot AvailableBindingDB 30130
References
  1. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C: Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008 Feb 14;51(3):347-72. doi: 10.1021/jm7009364. Epub 2008 Jan 9. [18181565 ]
General Function:
Cyclin-dependent protein serine/threonine kinase regulator activity
Specific Function:
Binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function.
Gene Name:
CKS1B
Uniprot ID:
P61024
Molecular Weight:
9660.14 Da
References
  1. Krishnan A, Hariharan R, Nair SA, Pillai MR: Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1. Biochem Pharmacol. 2008 May 15;75(10):1924-34. doi: 10.1016/j.bcp.2008.02.013. Epub 2008 Feb 17. [18371935 ]
General Function:
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 Pi turnover.
Gene Name:
CHRM3
Uniprot ID:
P20309
Molecular Weight:
66127.445 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory1 uMNot AvailableBindingDB 30130
References
  1. Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]
General Function:
Guanyl-nucleotide exchange factor 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 inhibition of adenylate cyclase.
Gene Name:
CHRM4
Uniprot ID:
P08173
Molecular Weight:
53048.65 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory2.9 uMNot AvailableBindingDB 30130
References
  1. Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]
General Function:
Opioid receptor activity
Specific Function:
Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria (By similarity).
Gene Name:
SIGMAR1
Uniprot ID:
Q99720
Molecular Weight:
25127.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.851 uMNot AvailableBindingDB 30130
References
  1. Myers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, Booth RG, Wyrick SD: Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor. J Med Chem. 1994 Nov 25;37(24):4109-17. [7990111 ]