Target Information

Target General Infomation
Target ID
T64591
Former ID
TTDS00399
Target Name
5-hydroxytryptamine receptor 3A
Gene Name
HTR3A
Synonyms
5-HT-3; 5-HT3A; 5-HT3R; 5HT3R; HTR3; Serotonin receptor 3A; Serotonin-gated ion channel receptor; HTR3A
Target Type
Successful
Disease Emesis [ICD9: 787; ICD10: R11]
Fibromyalgia [ICD9: 729.1; ICD10: M79.7]
Gastroesophageal reflux disease [ICD9: 140-229, 530; ICD10: K21]
Irritable bowel syndrome [ICD9: 564.1, 787.91; ICD10: A09, K58, K59.1]
Local anaesthetic [ICD10: R20.0]
Nausea [ICD10: R11]
Nausea; Vomiting [ICD9: 787, 787.0; ICD10: R11]
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 whenactivated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.
BioChemical Class
Neurotransmitter receptor
Target Validation
T64591
UniProt ID
P46098
Sequence
MLLWVQQALLALLLPTLLAQGEARRSRNTTRPALLRLSDYLLTNYRKGVRPVRDWRKPTT
VSIDVIVYAILNVDEKNQVLTTYIWYRQYWTDEFLQWNPEDFDNITKLSIPTDSIWVPDI
LINEFVDVGKSPNIPYVYIRHQGEVQNYKPLQVVTACSLDIYNFPFDVQNCSLTFTSWLH
TIQDINISLWRLPEKVKSDRSVFMNQGEWELLGVLPYFREFSMESSNYYAEMKFYVVIRR
RPLFYVVSLLLPSIFLMVMDIVGFYLPPNSGERVSFKITLLLGYSVFLIIVSDTLPATAI
GTPLIGVYFVVCMALLVISLAETIFIVRLVHKQDLQQPVPAWLRHLVLERIAWLLCLREQ
STSQRPPATSQATKTDDCSAMGNHCSHMGGPQDFEKSPRDRCSPPPPPREASLAVCGLLQ
ELSSIRQFLEKRDEIREVARDWLRVGSVLDKLLFHIYLLAVLAYSITLVMLWSIWQYA
Drugs and Mode of Action
Drug(s) Alosetron Drug Info Approved Irritable bowel syndrome [536224], [539447]
Dolasetron Drug Info Approved Nausea; Vomiting [536361]
Levetriacetam Drug Info Approved Fibromyalgia [536647]
Palonosetron Drug Info Approved Nausea; Vomiting [536361], [542509]
Procaine Drug Info Approved Local anaesthetic [551871]
Tropisetron Drug Info Approved Fibromyalgia [536647], [539678]
Cilansetron Drug Info Phase 3 Irritable bowel syndrome [536224], [539448]
ATI-17000 Drug Info Preclinical Irritable bowel syndrome [536224]
BEMESETRON Drug Info Discontinued in Phase 3 Discovery agent [544703]
Norcisapride Drug Info Discontinued in Phase 2 Gastroesophageal reflux disease [546263]
YM-114 Drug Info Discontinued in Phase 2 Nausea [545300]
AS-8112 Drug Info Terminated Emesis [546591]
Inhibitor (4-Quinolin-2-ylpiperazin-1-yl)acetic Acid Drug Info [530114]
1-(biphenyl-4-yl)-3-(4-(piperidin-1-yl)butyl)urea Drug Info [530912]
10,11-dihydro-5H-dibenzo[b,f]azepine Drug Info [529922]
2-(1H-Imidazol-4-ylmethyl)-4-phenyl-thiazole Drug Info [532034]
2-(4-Benzyl-piperazin-1-yl)-benzothiazole Drug Info [533917]
2-(4-Methyl-piperazin-1-yl)-quinoline Drug Info [525484]
3-(2-Amino-ethyl)-2-methyl-1H-indol-5-ol Drug Info [532034]
3alpha-(1'-Methyl-2'-Indolecarbonyloxy)-tropane Drug Info [530355]
3alpha-(2'-Indolecarbonyloxy)-nortropane Drug Info [530355]
4-((naphthalen-2-yloxy)methyl)piperidine Drug Info [530012]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [531079]
4-Benzoxazo-2-yl-1,4-diazabicyclo[3.2.2]nonane Drug Info [530609]
5,6-dichloro-3,4-dihydroquinazolin-2-amine Drug Info [529148]
5-chloro-3,4-dihydroquinazolin-2-amine Drug Info [529148]
6-(4-Methyl-piperazin-1-yl)-phenanthridine Drug Info [525484]
7-(piperidin-4-ylmethoxy)-2-naphthonitrile Drug Info [530012]
A-987306 Drug Info [529789]
BEMESETRON Drug Info [528702]
BRL-24682 Drug Info [526544]
CP-810123 Drug Info [530609]
FLUPENTIXOLE Drug Info [529922]
MESULERGINE Drug Info [534503]
Norcisapride Drug Info [530330]
PH-709829 Drug Info [529479]
QUIPAZINE Drug Info [530451]
SEROTONIN Drug Info [525484]
Antagonist (S)-zacopride Drug Info [526116]
Alosetron Drug Info [537217], [537382]
AS-8112 Drug Info [536188]
ATI-17000 Drug Info [536224]
Dolasetron Drug Info [537011]
Levetriacetam Drug Info [536647]
Palonosetron Drug Info [537311]
Procaine Drug Info [536543]
Tropisetron Drug Info [536647]
YM-114 Drug Info [534150], [551871]
[3H](S)-zacopride Drug Info [534304]
[3H]GR65630 Drug Info [528958]
[3H]granisetron Drug Info [534215]
[3H]LY278584 Drug Info [534033]
[3H]ramosetron Drug Info [533639]
Agonist 1-phenylbiguanide Drug Info [533742]
2-methyl-5-HT Drug Info [525930]
meta-chlorphenylbiguanide Drug Info [534584]
[3H]meta-chlorophenylbiguanide Drug Info [534584]
Modulator (allosteric modulator) 5-hydroxyindole Drug Info [529253]
trichloroethanol Drug Info [529227]
Blocker (channel blocker) bilobalide Drug Info [531440]
TMB-8 Drug Info [525521]
Modulator Cilansetron Drug Info
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Serotonergic synapse
NetPath Pathway IL2 Signaling Pathway
PANTHER Pathway 5HT3 type receptor mediated signaling pathway
Reactome Ligand-gated ion channel transport
WikiPathways SIDS Susceptibility Pathways
Iron uptake and transport
References
Ref 536224Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313.
Ref 536361Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20.
Ref 536647Emerging therapies for fibromyalgia. Expert Opin Emerg Drugs. 2008 Mar;13(1):53-62.
Ref 539447(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2296).
Ref 539448(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2297).
Ref 539678(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 260).
Ref 542509(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7486).
Ref 544703Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000675)
Ref 545300Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002741)
Ref 546263Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007174)
Ref 546591Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009088)
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 525484J Med Chem. 1999 May 6;42(9):1556-75.Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 2. Molecular basis of the intrinsic efficacy of arylpiperazine derivatives at the central 5-HT3 receptors.
Ref 525521Characterization of interaction of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester with Torpedo californica nicotinic acetylcholine receptor and 5-hydroxytryptamine3 receptor. J Pharmacol Exp Ther. 1999 Jul;290(1):129-35.
Ref 525930Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro. Eur J Pharmacol. 2000 Dec 8;409(2):195-201.
Ref 526116Pharmacological comparison of human homomeric 5-HT3A receptors versus heteromeric 5-HT3A/3B receptors. Neuropharmacology. 2001 Aug;41(2):282-4.
Ref 526544J Med Chem. 2003 Feb 27;46(5):702-15.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.
Ref 528702J Med Chem. 1992 Jan 24;35(2):310-9.Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Ref 528958Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome. J Pharmacol Sci. 2007 Jul;104(3):263-73.
Ref 529148Bioorg Med Chem Lett. 2008 Jan 1;18(1):256-61. Epub 2007 Oct 30.Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation.
Ref 529227Arginine 246 of the pretransmembrane domain 1 region alters 2,2,2-trichloroethanol action in the 5-hydroxytryptamine3A receptor. J Pharmacol Exp Ther. 2008 Mar;324(3):1011-8. Epub 2007 Dec 19.
Ref 529253The 5-HT3B subunit confers spontaneous channel opening and altered ligand properties of the 5-HT3 receptor. J Biol Chem. 2008 Mar 14;283(11):6826-31.
Ref 529479Bioorg Med Chem Lett. 2008 Jun 15;18(12):3611-5. Epub 2008 May 1.Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity.
Ref 529789J Med Chem. 2008 Nov 27;51(22):7094-8.cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
Ref 529922Eur J Med Chem. 2009 Jun;44(6):2667-72. Epub 2008 Dec 16.Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5-HT3A receptors.
Ref 530012Bioorg Med Chem Lett. 2009 Apr 15;19(8):2329-32. Epub 2009 Feb 20.Design and optimization of selective serotonin re-uptake inhibitors with high synthetic accessibility. Part 1.
Ref 530114J Med Chem. 2009 Jun 11;52(11):3548-62.Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structure-activity relationships.
Ref 530330Bioorg Med Chem Lett. 2009 Oct 1;19(19):5679-83. Epub 2009 Aug 8.mu-Opioid/5-HT4 dual pharmacologically active agents-efforts towards an effective opioid analgesic with less GI and respiratory side effects (Part I).
Ref 530355Bioorg Med Chem. 2009 Oct 1;17(19):6872-8. Epub 2009 Aug 20.Synthesis of heteroaromatic tropeines and heterogeneous binding to glycine receptors.
Ref 530451J Med Chem. 2009 Nov 12;52(21):6946-50.Novel, potent, and selective quinoxaline-based 5-HT(3) receptor ligands. 1. Further structure-activity relationships and pharmacological characterization.
Ref 530609J Med Chem. 2010 Feb 11;53(3):1222-37.Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models.
Ref 530912J Med Chem. 2010 Jun 10;53(11):4379-89.Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl) urea (SEN34625/WYE-103914).
Ref 531079J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Ref 531440Binding sites for bilobalide, diltiazem, ginkgolide, and picrotoxinin at the 5-HT3 receptor. Mol Pharmacol. 2011 Jul;80(1):183-90.
Ref 532034J Med Chem. 1990 Jan;33(1):13-6.Aromatic thiazole derivatives: structurally novel and selective serotonin-3 receptor antagonists.
Ref 533639Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species. Mol Pharmacol. 1995 Sep;48(3):407-16.
Ref 533742Allosteric interactions among agonists and antagonists at 5-hydroxytryptamine3 receptors. J Neurochem. 1995 Jul;65(1):104-10.
Ref 533917J Med Chem. 1994 Apr 29;37(9):1320-5.Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties.
Ref 534033Pharmacological and regional characterization of [3H]LY278584 binding sites in human brain. J Neurochem. 1993 Feb;60(2):730-7.
Ref 534150Effect of serotonin (5-HT)3-receptor antagonists YM060, YM114 (KAE-393), ondansetron and granisetron on 5-HT4 receptors and gastric emptying in rodents. Jpn J Pharmacol. 1995 Nov;69(3):205-14.
Ref 534215Characterization of a human 5-hydroxytryptamine3 receptor type A (h5-HT3R-AS) subunit stably expressed in HEK 293 cells. Br J Pharmacol. 1996 Jul;118(5):1237-45.
Ref 534304Autoradiographic distribution of [3H]-(S)-zacopride-labelled 5-HT3 receptors in human brain. J Neurol Sci. 1996 Dec;144(1-2):119-27.
Ref 534503J Med Chem. 1997 Oct 24;40(22):3670-8.Novel and highly potent 5-HT3 receptor agonists based on a pyrroloquinoxaline structure.
Ref 534584Different efficacy of specific agonists at 5-HT3 receptor splice variants: the role of the extra six amino acid segment. Br J Pharmacol. 1998 Feb;123(4):661-6.
Ref 536188Emerging drugs for chemotherapy-induced emesis. Expert Opin Emerg Drugs. 2006 Mar;11(1):137-51.
Ref 536224Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313.
Ref 536543Local anesthetics have different mechanisms and sites of action at recombinant 5-HT3 receptors. Reg Anesth Pain Med. 2007 Nov-Dec;32(6):462-70.
Ref 536647Emerging therapies for fibromyalgia. Expert Opin Emerg Drugs. 2008 Mar;13(1):53-62.
Ref 537011Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial.Lancet Oncol. 2009 Feb;10(2):115-24. Epub 2009 Jan 8.
Ref 537217Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clin Chim Acta. 2009 May;403(1-2):47-55. Epub 2009 Feb 4.
Ref 537311Management of postoperative nausea and vomiting: focus on palonosetron. Ther Clin Risk Manag. 2009 Feb;5(1):21-34. Epub 2009 Mar 26.
Ref 537382Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2009 Jul;104(7):1831-43; quiz 1844. Epub 2009 May 26.
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

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