T3DB: Ondansetron

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (15)XML

Targets (15)

Record Information

Version

2.0

Creation Date

2009-07-21 20:27:55 UTC

Update Date

2014-12-24 20:25:53 UTC

Accession Number

T3D2925

Identification

Common Name

Ondansetron

Class

Small Molecule

Description

Ondansetron is a well tolerated drug with few side effects. Headache, constipation, and dizziness are the most commonly reported side effects associated with its use. There have been no significant drug interactions reported with this drugs use. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system; Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly to treat nausea and vomiting following chemotherapy. Its effects are thought to be on both peripheral and central nerves. One part is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata, the other is a blockage of serotonin receptors in the chemoreceptor trigger zone. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors; A competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and has reported anxiolytic and neuroleptic properties; Ondansetron (INN) is a serotonin 5-HT3 receptor antagonist used mainly to treat nausea and vomiting following chemotherapy. Its effects are thought to be on both peripheral and central nerves. One part is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata, the other is a blockage of serotonin receptors in the chemoreceptor trigger zone. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Compound Type

Amide
Amine
Anti-Anxiety Agent
Antiemetic
Antipruritic
Antipsychotic Agent
Drug
Ester
Food Toxin
Metabolite
Organic Compound
Serotonin Antagonist
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
Zofran
Zofran odt
Zophren
Zudan
Zuplenz

Chemical Formula

C₁₈H₁₉N₃O

Average Molecular Mass

293.363 g/mol

Monoisotopic Mass

293.153 g/mol

CAS Registry Number

99614-02-5

IUPAC Name

9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3,4,9-tetrahydro-1H-carbazol-4-one

Traditional Name

ondansetron

SMILES

CN1C2=C(C3=CC=CC=C13)C(=O)C(CN1C=CN=C1C)CC2

InChI Identifier

InChI=1/C18H19N3O/c1-12-19-9-10-21(12)11-13-7-8-16-17(18(13)22)14-5-3-4-6-15(14)20(16)2/h3-6,9-10,13H,7-8,11H2,1-2H3

InChI Key

InChIKey=FELGMEQIXOGIFQ-UHFFFAOYNA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as carbazoles. Carbazoles are compounds containing a three ring system containing a pyrrole ring fused on either side to a benzene ring.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Indoles and derivatives

Sub Class

Carbazoles

Direct Parent

Carbazoles

Alternative Parents

Substituents

Carbazole
N-alkylindole
Indole
Aryl ketone
Aryl alkyl ketone
N-methylpyrrole
N-substituted imidazole
Substituted pyrrole
Benzenoid
Imidazole
Pyrrole
Azole
Vinylogous amide
Heteroaromatic compound
Ketone
Azacycle
Organic oxide
Organopnictogen compound
Organic nitrogen compound
Organooxygen compound
Organonitrogen compound
Organic oxygen compound
Hydrocarbon derivative
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

carbazoles (CHEBI:7773 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Liver

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	231 - 232°C
Boiling Point	Not Available
Solubility	Not Available
LogP	2.4

Predicted Properties

Property	Value	Source
Water Solubility	0.25 g/L	ALOGPS
logP	2.56	ALOGPS
logP	2.35	ChemAxon
logS	-3.1	ALOGPS
pKa (Strongest Acidic)	15.39	ChemAxon
pKa (Strongest Basic)	7.34	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	39.82 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	86.78 m³·mol⁻¹	ChemAxon
Polarizability	33.16 Å³	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-00nb-9840000000-3e06f3c6b7dfe3741b9d	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-0006-0590000000-1c293e5af06aedfb74e1	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-006x-0790000000-39dfc83ad8c54c21d83d	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-00e9-0900000000-9f75de47087ea727dbcc	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 50V, Positive	splash10-01b9-0900000000-908023356faf6f180af3	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-00e9-0900000000-5113a05488a50bd3517c	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-00ec-0950000000-99bd0224adfac797252e	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-0006-0090000000-b12ef22126884edee127	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Positive	splash10-00e9-0910000000-bc8f444f5a685a24b58b	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0006-0290000000-a83e2f6fa456e4784c8e	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-006x-0790000000-a881fb3942f2794a745a	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0006-0090000000-cd5ee2ea8a09e479ca82	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-03dl-1190000000-b8299468585346441088	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-001r-7930000000-39cdbd8680e338fc52d1	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0006-3090000000-6ea6246fc080e90b47b9	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-001i-9040000000-063a9351d8828458eb6a	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9000000000-67ae58fff567a97b5c75	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0006-0090000000-1ddcbe24b3692363c9e9	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0006-0090000000-92a569aa48de1bbd22ad	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-06r6-1950000000-4c010488c047e6167385	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0006-0090000000-6e00cbfb66b0b752aed9	2021-09-23	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-01ox-1090000000-975dfb36e43267beef53	2021-09-23	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-01vo-0290000000-9ef1b8637e2cdb4d9e6d	2021-09-23	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, CD₃OD, experimental)	Not Available	2012-12-05	View Spectrum
2D NMR	[¹H, ¹³C]-HSQC NMR Spectrum (2D, 600 MHz, CD₃OD, experimental)	Not Available	2012-12-05	View Spectrum

Toxicity Profile

Route of Exposure

Ondansetron is well absorbed after oral administration and undergoes limited first-pass metabolism.

Mechanism of Toxicity

Ondansetron is a selective serotonin 5-HT₃ receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT₃ receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT₃ receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone.

Metabolism

Hepatic Half Life: 5.7 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 prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, postoperation, and radiation. Also used for the treatment of postoperative nausea and vomiting.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Low blood pressure and fainting, sudden blindness, severe constipation

Treatment

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. (8)

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

103183

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Ondansetron

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Ondansetron

References

Synthesis Reference

Peter Bod, Kalman Harsanyi, Ferenc Trischler, Eva Fekecs, Attila Csehi, Bela Hegedus, Eva Mersich nee Donat, Gyorgyi Szabo nee Komlosi, Erika Horvath nee Sziki, “Process for preparing ondansetron.” U.S. Patent US5478949, issued September, 1990.

MSDS

Link

General References

Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D: A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med. 2002 Apr;39(4):397-403. [11919526 ]
Yilmaz HL, Yildizdas RD, Sertdemir Y: Clinical trial: oral ondansetron for reducing vomiting secondary to acute gastroenteritis in children--a double-blind randomized study. Aliment Pharmacol Ther. 2010 Jan;31(1):82-91. doi: 10.1111/j.1365-2036.2009.04145.x. Epub . [19758398 ]
Gregory RE, Ettinger DS: 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs. 1998 Feb;55(2):173-89. [9506240 ]
Gan TJ: Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? CNS Drugs. 2005;19(3):225-38. [15740177 ]
Tramer MR, Reynolds DJ, Moore RA, McQuay HJ: Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials. Anesthesiology. 1997 Dec;87(6):1277-89. [9416710 ]
Graves T: Ondansetron: a new entity in emesis control. DICP. 1990 Nov;24(11 Suppl):S51-4. [2148659 ]
Drugs.com [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. 5-hydroxytryptamine receptor 3A

General Function:: Voltage-gated potassium channel activity
Specific Function:: This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.
Gene Name:: HTR3A
Uniprot ID:: P46098
Molecular Weight:: 55279.835 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0028 uM	Not Available	BindingDB 50000493
Inhibitory	0.0034 uM	Not Available	BindingDB 50000493
Inhibitory	0.016 uM	Not Available	BindingDB 50000493
IC50	0.00009 uM	Not Available	BindingDB 50000493

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Artaiz I, Zazpe A, Del Rio J: Characterization of serotonergic mechanisms involved in the behavioural inhibition induced by 5-hydroxytryptophan in a modified light-dark test in mice. Behav Pharmacol. 1998 Mar;9(2):103-12. [10065930 ]
Fortuno A, Ballaz S, Del Rio J, Barber A: CCK-mediated response in the activation of 5-HT receptor types in the guinea-pig ileum. J Physiol Biochem. 1999 Jun;55(2):85-92. [10517265 ]
Llacer JM, Gallardo V, Delgado R, Parraga J, Martin D, Ruiz MA: X-ray diffraction and electron microscopy in the polymorphism study of ondansetron hydrochloride. Drug Dev Ind Pharm. 2001 Oct;27(9):899-908. [11763467 ]
Carvalho F, Macedo D, Bandeira I, Maldonado I, Salles L, Azevedo MF, Rocha MA Jr, Fregoneze JB, De Castro-e-Silva E: Central 5-HT3 receptor stimulation by m-CPBG increases blood glucose in rats. Horm Metab Res. 2002 Feb;34(2):55-61. [11972287 ]
Arcioni R, della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A: Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans. Anesth Analg. 2002 Jun;94(6):1553-7, table of contents. [12032025 ]
Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mork A, Stensbol TB: Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12. [21486038 ]
Yang Z, Fairfax DJ, Maeng JH, Masih L, Usyatinsky A, Hassler C, Isaacson S, Fitzpatrick K, DeOrazio RJ, Chen J, Harding JP, Isherwood M, Dobritsa S, Christensen KL, Wierschke JD, Bliss BI, Peterson LH, Beer CM, Cioffi C, Lynch M, Rennells WM, Richards JJ, Rust T, Khmelnitsky YL, Cohen ML, Manning DD: Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6538-41. doi: 10.1016/j.bmcl.2010.09.038. Epub 2010 Sep 16. [20889341 ]
Rizzi JP, Nagel AA, Rosen T, McLean S, Seeger T: An initial three-component pharmacophore for specific serotonin-3 receptor ligands. J Med Chem. 1990 Oct;33(10):2721-5. [2145434 ]
Rosen T, Nagel AA, Rizzi JP, Ives JL, Daffeh JB, Ganong AH, Guarino K, Heym J, McLean S, Nowakowski JT, et al.: Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists. J Med Chem. 1990 Oct;33(10):2715-20. [2213824 ]
Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D: A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med. 2002 Apr;39(4):397-403. [11919526 ]

Target Details

2. 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

Type	Value	Assay Type	Assay Source
IC50	0.4 uM	Not Available	BindingDB 50000493
IC50	0.81283 uM	Not Available	BindingDB 50000493
IC50	0.813 uM	Not Available	BindingDB 50000493

References

Yang Z, Fairfax DJ, Maeng JH, Masih L, Usyatinsky A, Hassler C, Isaacson S, Fitzpatrick K, DeOrazio RJ, Chen J, Harding JP, Isherwood M, Dobritsa S, Christensen KL, Wierschke JD, Bliss BI, Peterson LH, Beer CM, Cioffi C, Lynch M, Rennells WM, Richards JJ, Rust T, Khmelnitsky YL, Cohen ML, Manning DD: Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6538-41. doi: 10.1016/j.bmcl.2010.09.038. Epub 2010 Sep 16. [20889341 ]
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 ]
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 ]
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 ]

3. Serotonin Receptors (Protein Group)

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.
Included Proteins:: P08908 , P28222 , P28221 , P28566 , P30939 , P28223 , P41595 , P28335 , P46098 , O95264 , Q8WXA8 , Q70Z44 , A5X5Y0 , Q13639 , P50406 , P34969

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0076 uM	Not Available	BindingDB 50000493
Inhibitory	0.012 uM	Not Available	BindingDB 50000493
Dissociation	0.0000794 uM	Not Available	BindingDB 50000493
Dissociation	0.000398 uM	Not Available	BindingDB 50000493
Dissociation	0.05012 uM	Not Available	BindingDB 50000493

References

Hibert MF, Hoffmann R, Miller RC, Carr AA: Conformation-activity relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site. J Med Chem. 1990 Jun;33(6):1594-600. [2342053 ]
Kishibayashi N, Miwa Y, Hayashi H, Ishii A, Ichikawa S, Nonaka H, Yokoyama T, Suzuki F: 5-HT3 receptor antagonists. 3. Quinoline derivatives which may be effective in the therapy of irritable bowel syndrome. J Med Chem. 1993 Oct 29;36(22):3286-92. [8230119 ]
Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G, Tran O, Wright N, Gordon JC: The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist. Bioorg Med Chem Lett. 2001 Feb 12;11(3):319-21. [11212100 ]

Target Details

4. Multidrug and toxin extrusion protein 1

General Function:: Monovalent cation:proton antiporter activity
Specific Function:: Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and also the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a new platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes.
Gene Name:: SLC47A1
Uniprot ID:: Q96FL8
Molecular Weight:: 61921.585 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	0.03 uM	Not Available	BindingDB 50000493
IC50	0.15 uM	Not Available	BindingDB 50000493
IC50	0.16 uM	Not Available	BindingDB 50000493

References

Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
Kido Y, Matsson P, Giacomini KM: Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem. 2011 Jul 14;54(13):4548-58. doi: 10.1021/jm2001629. Epub 2011 Jun 8. [21599003 ]

Target Details

5. Multidrug and toxin extrusion protein 2

General Function:: Drug transmembrane transporter activity
Specific Function:: Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, and ganciclovir. Responsible for the secretion of cationic drugs across the brush border membranes.
Gene Name:: SLC47A2
Uniprot ID:: Q86VL8
Molecular Weight:: 65083.915 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	0.3 uM	Not Available	BindingDB 50000493
IC50	6.9 uM	Not Available	BindingDB 50000493

References

Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
Kido Y, Matsson P, Giacomini KM: Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem. 2011 Jul 14;54(13):4548-58. doi: 10.1021/jm2001629. Epub 2011 Jun 8. [21599003 ]

Target Details

6. Neuronal acetylcholine receptor subunit alpha-4

General Function:: Ligand-gated ion channel activity
Specific Function:: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.
Gene Name:: CHRNA4
Uniprot ID:: P43681
Molecular Weight:: 69956.47 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	46 uM	Not Available	BindingDB 50000493
IC50	66 uM	Not Available	BindingDB 50000493

References

Papke RL, Porter Papke JK, Rose GM: Activity of alpha7-selective agonists at nicotinic and serotonin 5HT3 receptors expressed in Xenopus oocytes. Bioorg Med Chem Lett. 2004 Apr 19;14(8):1849-53. [15050614 ]
Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G, Tran O, Wright N, Gordon JC: The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist. Bioorg Med Chem Lett. 2001 Feb 12;11(3):319-21. [11212100 ]

Target Details

7. Solute carrier family 22 member 1

General Function:: Secondary active organic cation transmembrane transporter activity
Specific Function:: Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin-dependent kinase II and LCK tyrosine kinase.
Gene Name:: SLC22A1
Uniprot ID:: O15245
Molecular Weight:: 61153.345 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>100 uM	Not Available	BindingDB 50000493
IC50	>300 uM	Not Available	BindingDB 50000493

References

Kido Y, Matsson P, Giacomini KM: Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem. 2011 Jul 14;54(13):4548-58. doi: 10.1021/jm2001629. Epub 2011 Jun 8. [21599003 ]
Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]

Target Details

8. Solute carrier family 22 member 2

General Function:: Quaternary ammonium group transmembrane transporter activity
Specific Function:: Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity.
Gene Name:: SLC22A2
Uniprot ID:: O15244
Molecular Weight:: 62579.99 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	0.89 uM	Not Available	BindingDB 50000493
IC50	1.7 uM	Not Available	BindingDB 50000493

References

Kido Y, Matsson P, Giacomini KM: Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem. 2011 Jul 14;54(13):4548-58. doi: 10.1021/jm2001629. Epub 2011 Jun 8. [21599003 ]
Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]

Target Details

9. 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

van Wijngaarden I, Tulp MT, Soudijn W: The concept of selectivity in 5-HT receptor research. Eur J Pharmacol. 1990 Jun 12;188(6):301-12. [2164935 ]

Target Details

10. 5-hydroxytryptamine receptor 1B

General Function:: Serotonin receptor activity
Specific Function:: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as 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, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries.
Gene Name:: HTR1B
Uniprot ID:: P28222
Molecular Weight:: 43567.535 Da

References

van Wijngaarden I, Tulp MT, Soudijn W: The concept of selectivity in 5-HT receptor research. Eur J Pharmacol. 1990 Jun 12;188(6):301-12. [2164935 ]

Target Details

11. 5-hydroxytryptamine receptor 4

General Function:: Serotonin receptor activity
Specific Function:: This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase.
Gene Name:: HTR4
Uniprot ID:: Q13639
Molecular Weight:: 43760.975 Da

References

van Wijngaarden I, Tulp MT, Soudijn W: The concept of selectivity in 5-HT receptor research. Eur J Pharmacol. 1990 Jun 12;188(6):301-12. [2164935 ]

Target Details

12. 5-hydroxytryptamine receptor 6

General Function:: Serotonin receptor activity
Specific Function:: This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. It has a high affinity for tricyclic psychotropic drugs (By similarity). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of TOR signaling (PubMed:23027611).
Gene Name:: HTR6
Uniprot ID:: P50406
Molecular Weight:: 46953.625 Da

References

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

Target Details

13. 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	11 uM	Not Available	BindingDB 50000493

References

Yang Z, Fairfax DJ, Maeng JH, Masih L, Usyatinsky A, Hassler C, Isaacson S, Fitzpatrick K, DeOrazio RJ, Chen J, Harding JP, Isherwood M, Dobritsa S, Christensen KL, Wierschke JD, Bliss BI, Peterson LH, Beer CM, Cioffi C, Lynch M, Rennells WM, Richards JJ, Rust T, Khmelnitsky YL, Cohen ML, Manning DD: Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6538-41. doi: 10.1016/j.bmcl.2010.09.038. Epub 2010 Sep 16. [20889341 ]

Target Details

14. Mu-type opioid receptor

General Function:: Voltage-gated calcium channel activity
Specific Function:: Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects. Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.
Gene Name:: OPRM1
Uniprot ID:: P35372
Molecular Weight:: 44778.855 Da

References

van Wijngaarden I, Tulp MT, Soudijn W: The concept of selectivity in 5-HT receptor research. Eur J Pharmacol. 1990 Jun 12;188(6):301-12. [2164935 ]

Target Details

15. Solute carrier family 22 member 3

General Function:: Toxin transporter activity
Specific Function:: Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
Gene Name:: SLC22A3
Uniprot ID:: O75751
Molecular Weight:: 61279.485 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	17.4 uM	Not Available	BindingDB 50000493

References

Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]

Ondansetron (T3D2925)

Structure for T3D2925: Ondansetron

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