T3DB: Cisapride

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (11)XML

Targets (11)

Record Information

Version

2.0

Creation Date

2009-07-21 20:27:14 UTC

Update Date

2014-12-24 20:25:52 UTC

Accession Number

T3D2836

Identification

Common Name

Cisapride

Class

Small Molecule

Description

In many countries (including Canada) cisapride has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to cisapride, which predisposes to arrhythmias. The FDA issued a warning letter regarding this risk to health care professionals and patients.

Compound Type

Amide
Amine
Anti-Ulcer Agent
Drug
Ester
Ether
Gastrointestinal Agent
Metabolite
Organic Compound
Organochloride
Organofluoride
Prokinetic Agent
Serotonin Agonist
Serotonin Receptor Agonist
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
(+-)-Cisapride
4-amino-5-chloro-N-(1-(3-(4-Fluorophenoxy)propyl)-3-methoxypiperidin-4-yl)-2-methoxybenzamide
4-Amino-5-chloro-N-{1-[3-(4-fluoro-phenoxy)-propyl]-3-methoxy-piperidin-4-yl}-2-methoxy-benzamide
cis-4-amino-5-chloro-N-(1-(3-(P-Fluorophenoxy)propyl)-3-methoxy-4-piperidyl)-O-anisamide
cis-4-amino-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-methoxybenzamide
cis-4-amino-5-chloro-N-{1-[3-(P-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-O-anisamide
Cisaprid
Cisaprida
Cisapridum
Enteropride
Kinestase
Prepulsid
Pridesia
Propulsid
Propulsid Quicksolv

Chemical Formula

C₂₃H₂₉ClFN₃O₄

Average Molecular Mass

465.945 g/mol

Monoisotopic Mass

465.183 g/mol

CAS Registry Number

81098-60-4

IUPAC Name

4-amino-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide

Traditional Name

(+-)-cisapride

SMILES

[H][C@@]1(CN(CCCOC2=CC=C(F)C=C2)CC[C@@]1([H])N=C(O)C1=C(OC)C=C(N)C(Cl)=C1)OC

InChI Identifier

InChI=1S/C23H29ClFN3O4/c1-30-21-13-19(26)18(24)12-17(21)23(29)27-20-8-10-28(14-22(20)31-2)9-3-11-32-16-6-4-15(25)5-7-16/h4-7,12-13,20,22H,3,8-11,14,26H2,1-2H3,(H,27,29)/t20-,22+/m1/s1

InChI Key

InChIKey=DCSUBABJRXZOMT-IRLDBZIGSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as aminobenzamides. These are organic compounds containing a benzamide moiety with an amine group attached to the benzene ring.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Benzoic acids and derivatives

Direct Parent

Aminobenzamides

Alternative Parents

Substituents

Aminobenzamide
Halobenzoic acid or derivatives
3-halobenzoic acid or derivatives
Aminophenyl ether
Methoxyaniline
Benzamide
Phenoxy compound
Anisole
Methoxybenzene
Aniline or substituted anilines
Benzoyl
Phenol ether
Alkyl aryl ether
Halobenzene
Fluorobenzene
Chlorobenzene
Aryl chloride
Aryl fluoride
Aryl halide
Piperidine
Amino acid or derivatives
Tertiary aliphatic amine
Carboxamide group
Tertiary amine
Secondary carboxylic acid amide
Azacycle
Organoheterocyclic compound
Carboxylic acid derivative
Dialkyl ether
Ether
Organic oxygen compound
Organonitrogen compound
Organooxygen compound
Primary amine
Amine
Organic nitrogen compound
Hydrocarbon derivative
Organofluoride
Organopnictogen compound
Organic oxide
Organochloride
Organohalogen compound
Aromatic heteromonocyclic compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

piperidines (CHEBI:3720 )
organofluorine compound (CHEBI:3720 )
aromatic ether (CHEBI:3720 )
substituted aniline (CHEBI:3720 )
benzamides (CHEBI:3720 )
monochlorobenzenes (CHEBI:3720 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

serotonergic agonist

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	110°C
Boiling Point	Not Available
Solubility	2.71 mg/L
LogP	3.3

Predicted Properties

Property	Value	Source
Water Solubility	0.012 g/L	ALOGPS
logP	2.95	ALOGPS
logP	2.49	ChemAxon
logS	-4.6	ALOGPS
pKa (Strongest Acidic)	14.58	ChemAxon
pKa (Strongest Basic)	8.24	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	6	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	86.05 Å²	ChemAxon
Rotatable Bond Count	9	ChemAxon
Refractivity	122.93 m³·mol⁻¹	ChemAxon
Polarizability	49.11 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-001i-2922000000-0772f474daac82b426ee	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
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-qTof , Positive	splash10-001i-0980000000-a0df861122e90da3494b	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-001i-0980000000-a0df861122e90da3494b	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-0159-0710900000-262b97df953edaab4cfa	2017-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0159-0111900000-61265dea2a01bd8e8378	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-001i-0943300000-cdcfabdf19797140d795	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0006-9861100000-46b94051a1f1227c9363	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03di-0400900000-c6cda5b55f88160e99de	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-03di-0921500000-6011948830548e90b8dc	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-03di-2910000000-5144f15cb7a70d64b8a3	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-014i-0001900000-8df7d19bd80f8e92fe73	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0gb9-0439600000-d40cbd486ff327890e07	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-03ea-4902100000-c20a14020bf3f34d23dd	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03di-0100900000-10eb08fa13f12fb9bc9d	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-03di-5915600000-de23551ac41099e763f9	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0il0-9411000000-a20e7213ffcaf2d0f91f	2021-10-11	View Spectrum

Toxicity Profile

Route of Exposure

Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%.

Mechanism of Toxicity

Cisapride acts through the stimulation of the serotonin 5-HT₄ receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit.

Metabolism

Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme. Half Life: 6-12 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 symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Diarrhea, upset stomach, stomach discomfort, vision changes, constipation.

Treatment

In instances of overdose, patients should be evaluated for possible QT prolongation and ventricular arrhythmias, including torsades de pointes. Treatment should include gastric lavage and/or activated charcoal, close observation and general supportive measures. (3)

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

3720

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Cisapride

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Cisapride

References

Synthesis Reference

Alfons Gaston Maria De Knaep, Luc Jozef Raphael Moens, Max Rey, “Synthesis of cisapride.” U.S. Patent US6218542, issued January, 1988.

MSDS

Link

General References

Pearce RE, Gotschall RR, Kearns GL, Leeder JS: Cytochrome P450 Involvement in the biotransformation of cisapride and racemic norcisapride in vitro: differential activity of individual human CYP3A isoforms. Drug Metab Dispos. 2001 Dec;29(12):1548-54. [11717173 ]
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. 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
Inhibitory	0.029 uM	Not Available	BindingDB 50005836
IC50	0.00646 uM	Not Available	BindingDB 50005836
IC50	0.0065 uM	Not Available	BindingDB 50005836
IC50	0.03981 uM	Not Available	BindingDB 50005836
IC50	0.04 uM	Not Available	BindingDB 50005836
IC50	0.045 uM	Not Available	BindingDB 50005836
IC50	0.047 uM	Not Available	BindingDB 50005836
IC50	0.05 uM	Not Available	BindingDB 50005836

References

Walker BD, Singleton CB, Bursill JA, Wyse KR, Valenzuela SM, Qiu MR, Breit SN, Campbell TJ: Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states. Br J Pharmacol. 1999 Sep;128(2):444-50. [10510456 ]
Chen J, Seebohm G, Sanguinetti MC: Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12461-6. Epub 2002 Sep 3. [12209010 ]
Lin J, Guo J, Gang H, Wojciechowski P, Wigle JT, Zhang S: Intracellular K+ is required for the inactivation-induced high-affinity binding of cisapride to HERG channels. Mol Pharmacol. 2005 Sep;68(3):855-65. Epub 2005 Jun 20. [15967876 ]
Perrio M, Voss S, Shakir SA: Application of the bradford hill criteria to assess the causality of cisapride-induced arrhythmia: a model for assessing causal association in pharmacovigilance. Drug Saf. 2007;30(4):333-46. [17408310 ]
Mohammad S, Zhou Z, Gong Q, January CT: Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol. 1997 Nov;273(5 Pt 2):H2534-8. [9374794 ]
Ermondi G, Visentin S, Caron G: GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers. Eur J Med Chem. 2009 May;44(5):1926-32. doi: 10.1016/j.ejmech.2008.11.009. Epub 2008 Nov 28. [19110341 ]
Cavalli A, Poluzzi E, De Ponti F, Recanatini M: Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers. J Med Chem. 2002 Aug 29;45(18):3844-53. [12190308 ]
Rajamani R, Tounge BA, Li J, Reynolds CH: A two-state homology model of the hERG K+ channel: application to ligand binding. Bioorg Med Chem Lett. 2005 Mar 15;15(6):1737-41. [15745831 ]
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 ]
Pearlstein RA, Vaz RJ, Kang J, Chen XL, Preobrazhenskaya M, Shchekotikhin AE, Korolev AM, Lysenkova LN, Miroshnikova OV, Hendrix J, Rampe D: Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches. Bioorg Med Chem Lett. 2003 May 19;13(10):1829-35. [12729675 ]
Pearlstein R, Vaz R, Rampe D: Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior. J Med Chem. 2003 May 22;46(11):2017-22. [12747773 ]
Imai YN, Ryu S, Oiki S: Docking model of drug binding to the human ether-a-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach. J Med Chem. 2009 Mar 26;52(6):1630-8. doi: 10.1021/jm801236n. [19260734 ]
Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC: A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12329-33. [11005845 ]
Wang J, Della Penna K, Wang H, Karczewski J, Connolly TM, Koblan KS, Bennett PB, Salata JJ: Functional and pharmacological properties of canine ERG potassium channels. Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H256-67. Epub 2002 Oct 3. [12388285 ]
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 ]

Target Details

2. 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

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0143 uM	Not Available	BindingDB 50005836

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Nagakura Y, Akuzawa S, Miyata K, Kamato T, Suzuki T, Ito H, Yamaguchi T: Pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-HT4 receptor versus human 5-HT3 receptor. Pharmacol Res. 1999 May;39(5):375-82. [10328995 ]
Crema F, Modini C, Croci T, Langlois M, de Ponti F: Intestinal prokinesia by two esters of 4-amino-5-chloro-2- methoxybenzoic acid: involvement of 5-hydroxytryptamine-4 receptors and dissociation from cardiac effects in vivo. J Pharmacol Exp Ther. 1999 Mar;288(3):1045-52. [10027842 ]
Rahme MM, Cotter B, Leistad E, Wadhwa MK, Mohabir R, Ford AP, Eglen RM, Feld GK: Electrophysiological and antiarrhythmic effects of the atrial selective 5-HT(4) receptor antagonist RS-100302 in experimental atrial flutter and fibrillation. Circulation. 1999 Nov 9;100(19):2010-7. [10556228 ]
Bharucha AE, Camilleri M, Haydock S, Ferber I, Burton D, Cooper S, Tompson D, Fitzpatrick K, Higgins R, Zinsmeister AR: Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans. Gut. 2000 Nov;47(5):667-74. [11034583 ]
Bach T, Syversveen T, Kvingedal AM, Krobert KA, Brattelid T, Kaumann AJ, Levy FO: 5HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle. Naunyn Schmiedebergs Arch Pharmacol. 2001 Feb;363(2):146-60. [11218067 ]
Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S: Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity. J Med Chem. 2003 Feb 27;46(5):702-15. [12593651 ]

Target Details

3. 5-hydroxytryptamine receptor 2A

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

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.0102 uM	Not Available	BindingDB 50005836

References

Nieto JE, Snyder JR, Kollias-Baker C, Stanley S: In vitro effects of 5-hydroxytryptamine and cisapride on the circular smooth muscle of the jejunum of horses. Am J Vet Res. 2000 Dec;61(12):1561-5. [11131599 ]
Cushing DJ, Cohen ML: Serotonin-induced contraction in porcine coronary artery: use of ergolines to support vascular 5-hydroxytryptamine2-receptor heterogeneity. J Pharmacol Exp Ther. 1993 Jan;264(1):193-200. [8423526 ]
Beubler E, Coupar IM, Hardcastle J, Hardcastle PT: Stimulatory effects of 5-hydroxytryptamine on fluid secretion and transmural potential difference in rat small intestine are mediated by different receptor subtypes. J Pharm Pharmacol. 1990 Jan;42(1):35-9. [1969947 ]
Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL: Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences. J Pharmacol Exp Ther. 1996 Feb;276(2):720-7. [8632342 ]

Target Details

4. 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

References

Nagakura Y, Akuzawa S, Miyata K, Kamato T, Suzuki T, Ito H, Yamaguchi T: Pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-HT4 receptor versus human 5-HT3 receptor. Pharmacol Res. 1999 May;39(5):375-82. [10328995 ]
Talley NJ: Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. Aliment Pharmacol Ther. 1992 Jun;6(3):273-89. [1600046 ]
de Ridder WJ, Schuurkes JA: Cisapride and 5-hydroxytryptamine enhance motility in the canine antrum via separate pathways, not involving 5-hydroxytryptamine1,2,3,4 receptors. J Pharmacol Exp Ther. 1993 Jan;264(1):79-88. [8093733 ]
Haga N, Suzuki H, Shiba Y, Mochiki E, Mizumoto A, Itoh Z: Effect of TKS159, a novel 5-hydroxytryptamine4 agonist, on gastric contractile activity in conscious dogs. Neurogastroenterol Motil. 1998 Aug;10(4):295-303. [9697104 ]

Target Details

5. 5-hydroxytryptamine receptor 2B

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

Type	Value	Assay Type	Assay Source
Inhibitory	0.0623 uM	Not Available	BindingDB 50005836

References

Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL: Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences. J Pharmacol Exp Ther. 1996 Feb;276(2):720-7. [8632342 ]

Target Details

6. 5-hydroxytryptamine receptor 2C

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

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.508 uM	Not Available	BindingDB 50005836

References

Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL: Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences. J Pharmacol Exp Ther. 1996 Feb;276(2):720-7. [8632342 ]

Target Details

7. Beta-1 adrenergic receptor

General Function:: Receptor signaling protein activity
Specific Function:: Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Mediates Ras activation through G(s)-alpha- and cAMP-mediated signaling.
Gene Name:: ADRB1
Uniprot ID:: P08588
Molecular Weight:: 51322.1 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>10 uM	Not Available	BindingDB 50005836

References

Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC: Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists. J Med Chem. 2006 Feb 9;49(3):1125-39. [16451077 ]

Target Details

8. D(1A) dopamine receptor

General Function:: G-protein coupled amine receptor activity
Specific Function:: Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Gene Name:: DRD1
Uniprot ID:: P21728
Molecular Weight:: 49292.765 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	1.7 uM	Not Available	BindingDB 50005836

References

Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC: Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists. J Med Chem. 2006 Feb 9;49(3):1125-39. [16451077 ]

Target Details

9. D(2) dopamine receptor

General Function:: Potassium channel regulator activity
Specific Function:: Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name:: DRD2
Uniprot ID:: P14416
Molecular Weight:: 50618.91 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	0.227 uM	Not Available	BindingDB 50005836

References

Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC: Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists. J Med Chem. 2006 Feb 9;49(3):1125-39. [16451077 ]

10. 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	0.152 uM	Not Available	BindingDB 50005836

References

Langlois M, Fischmeister R: 5-HT4 receptor ligands: applications and new prospects. J Med Chem. 2003 Jan 30;46(3):319-44. [12540230 ]

Target Details

11. Ubiquitin-conjugating enzyme E2 N

General Function:: Ubiquitin-protein transferase activity
Specific Function:: The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes.
Gene Name:: UBE2N
Uniprot ID:: P61088
Molecular Weight:: 17137.625 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>20 uM	Not Available	BindingDB 50005836

References

Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]

Cisapride (T3D2836)

Structure for T3D2836: Cisapride

Targets

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