Target Information

Target General Information

Target ID

T64591 (Former ID: TTDS00399)

Target Name

5-HT 3A receptor (HTR3A)

Synonyms

Serotonin-gated ion channel receptor; Serotonin receptor 3A; HTR3; 5HT3R; 5-hydroxytryptamine receptor 3A; 5-HT3RA; 5-HT3A; 5-HT3-A; 5-HT 3A

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Gene Name

HTR3A

Target Type

Successful target

[1]

Disease

[+] 5 Target-related Diseases

Chronic pain [ICD-11: MG30]

Corneal disease [ICD-11: 9A76-9A78]

Epilepsy/seizure [ICD-11: 8A61-8A6Z]

Irritable bowel syndrome [ICD-11: DD91]

Nausea/vomiting [ICD-11: MD90]

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.

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BioChemical Class

GPCR rhodopsin

UniProt ID

5HT3A_HUMAN

Sequence

MLLWVQQALLALLLPTLLAQGEARRSRNTTRPALLRLSDYLLTNYRKGVRPVRDWRKPTT
VSIDVIVYAILNVDEKNQVLTTYIWYRQYWTDEFLQWNPEDFDNITKLSIPTDSIWVPDI
LINEFVDVGKSPNIPYVYIRHQGEVQNYKPLQVVTACSLDIYNFPFDVQNCSLTFTSWLH
TIQDINISLWRLPEKVKSDRSVFMNQGEWELLGVLPYFREFSMESSNYYAEMKFYVVIRR
RPLFYVVSLLLPSIFLMVMDIVGFYLPPNSGERVSFKITLLLGYSVFLIIVSDTLPATAI
GTPLIGVYFVVCMALLVISLAETIFIVRLVHKQDLQQPVPAWLRHLVLERIAWLLCLREQ
STSQRPPATSQATKTDDCSAMGNHCSHMGGPQDFEKSPRDRCSPPPPPREASLAVCGLLQ
ELSSIRQFLEKRDEIREVARDWLRVGSVLDKLLFHIYLLAVLAYSITLVMLWSIWQYA

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

ADReCS ID

BADD_A00273 ; BADD_A02979 ; BADD_A04075 ; BADD_A04623

HIT2.0 ID

T39GNZ

Drugs and Modes of Action

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Approved Drug(s)

[+] 7 Approved Drugs

Alosetron

Drug Info

Approved

Irritable bowel syndrome

[2], [3]

Dolasetron

Drug Info

Approved

Nausea

[4]

Levetiracetam

Drug Info

Approved

Fibromyalgia

[5]

Palonosetron

Drug Info

Approved

Nausea

[4], [6]

Palonosetron + fosnetupitant

Drug Info

Approved

Chemotherapy-induced nausea

[7]

Procaine

Drug Info

Approved

Anaesthesia

[8]

Tropisetron

Drug Info

Approved

Fibromyalgia

[5], [9]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Cilansetron

Drug Info

Phase 3

Irritable bowel syndrome

[3], [10]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

Norcisapride

Drug Info

Discontinued in Phase 2

Gastroesophageal reflux disease

[11]

YM-114

Drug Info

Discontinued in Phase 2

Nausea

[12]

AS-8112

Drug Info

Terminated

Vomiting

[13]

BP4.879a

Drug Info

Terminated

Schizophrenia

[14]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

ATI-17000

Drug Info

Preclinical

Irritable bowel syndrome

[3]

Mode of Action

[+] 6 Modes of Action

Antagonist

[+] 16 Antagonist drugs

Alosetron

Drug Info

[15], [16]

Dolasetron

Drug Info

[17]

Levetiracetam

Drug Info

[5]

Palonosetron

Drug Info

[18]

Palonosetron + fosnetupitant

Drug Info

[7]

Procaine

Drug Info

[1]

Tropisetron

Drug Info

[5]

YM-114

Drug Info

[8], [22]

ATI-17000

Drug Info

[3]

AS-8112

Drug Info

[23]

BP4.879a

Drug Info

[24]

(S)-zacopride

Drug Info

[26]

[3H](S)-zacopride

Drug Info

[49]

[3H]GR65630

Drug Info

[50]

[3H]granisetron

Drug Info

[51]

[3H]ramosetron

Drug Info

[52]

Modulator

[+] 1 Modulator drugs

Cilansetron

Drug Info

[19]

Inhibitor

[+] 25 Inhibitor drugs

BEMESETRON

Drug Info

[20]

Norcisapride

Drug Info

[21]

(4-Quinolin-2-ylpiperazin-1-yl)acetic Acid

Drug Info

[25]

1-(biphenyl-4-yl)-3-(4-(piperidin-1-yl)butyl)urea

Drug Info

[27]

10,11-dihydro-5H-dibenzo[b,f]azepine

Drug Info

[29]

2-(1H-Imidazol-4-ylmethyl)-4-phenyl-thiazole

Drug Info

[30]

2-(4-Benzyl-piperazin-1-yl)-benzothiazole

Drug Info

[31]

2-(4-Methyl-piperazin-1-yl)-quinoline

Drug Info

[32]

3alpha-(1'-Methyl-2'-Indolecarbonyloxy)-tropane

Drug Info

[34]

3alpha-(2'-Indolecarbonyloxy)-nortropane

Drug Info

[34]

4-((naphthalen-2-yloxy)methyl)piperidine

Drug Info

[35]

4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one

Drug Info

[36]

4-Benzoxazo-2-yl-1,4-diazabicyclo[3.2.2]nonane

Drug Info

[37]

5,6-dichloro-3,4-dihydroquinazolin-2-amine

Drug Info

[38]

5-chloro-3,4-dihydroquinazolin-2-amine

Drug Info

[38]

6-(4-Methyl-piperazin-1-yl)-phenanthridine

Drug Info

[32]

7-(piperidin-4-ylmethoxy)-2-naphthonitrile

Drug Info

[35]

A-987306

Drug Info

[40]

BRL-24682

Drug Info

[42]

CP-810123

Drug Info

[37]

FLUPENTIXOLE

Drug Info

[29]

MESULERGINE

Drug Info

[43]

PH-709829

Drug Info

[45]

QUIPAZINE

Drug Info

[46]

SEROTONIN

Drug Info

[32]

Agonist

[+] 3 Agonist drugs

1-phenylbiguanide

Drug Info

[28]

2-methyl-5-HT

Drug Info

[33]

meta-chlorphenylbiguanide

Drug Info

[44]

Modulator (allosteric modulator)

[+] 2 Modulator (allosteric modulator) drugs

5-hydroxyindole

Drug Info

[39]

trichloroethanol

Drug Info

[48]

Blocker (channel blocker)

[+] 2 Blocker (channel blocker) drugs

bilobalide

Drug Info

[41]

TMB-8

Drug Info

[47]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Pathway Affiliation

There is no similarity protein (E value < 0.005) for this target

KEGG Pathway	Pathway ID	Affiliated Target
Serotonergic synapse	hsa04726	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Taste transduction	hsa04742	Affiliated Target
Class: Organismal Systems => Sensory system	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 1 KEGG Pathways

Serotonergic synapse

NetPath Pathway

[+] 1 NetPath Pathways

IL2 Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

5HT3 type receptor mediated signaling pathway

Reactome

[+] 1 Reactome Pathways

Ligand-gated ion channel transport

WikiPathways

[+] 2 WikiPathways

SIDS Susceptibility Pathways

Iron uptake and transport

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Local 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 2

URL: 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 3

Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313.

REF 4

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 5

Emerging therapies for fibromyalgia. Expert Opin Emerg Drugs. 2008 Mar;13(1):53-62.

REF 6

REF 7

2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.

REF 8

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 9

REF 10

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007174)

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002741)

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009088)

REF 14

The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.

REF 15

Efficacy 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.

REF 16

Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clin Chim Acta. 2009 May;403(1-2):47-55.

REF 17

Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, do... Lancet Oncol. 2009 Feb;10(2):115-24.

REF 18

Management of postoperative nausea and vomiting: focus on palonosetron. Ther Clin Risk Manag. 2009 Feb;5(1):21-34.

REF 19

Cilansetron: a new serotonergic agent for the irritable bowel syndrome with diarrhoea.Expert Opin Investig Drugs.2005 Feb;14(2):185-93.

REF 20

Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships. J Med Chem. 1992 Jan 24;35(2):310-9.

REF 21

mu-Opioid/5-HT4 dual pharmacologically active agents-efforts towards an effective opioid analgesic with less GI and respiratory side effects (Part I). Bioorg Med Chem Lett. 2009 Oct 1;19(19):5679-83.

REF 22

Effect 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 23

Emerging drugs for chemotherapy-induced emesis. Expert Opin Emerg Drugs. 2006 Mar;11(1):137-51.

REF 24

Pharmacological and regional characterization of [3H]LY278584 binding sites in human brain. J Neurochem. 1993 Feb;60(2):730-7.

REF 25

Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structure-activity relationships. J Med Chem. 2009 Jun 11;52(11):3548-62.

REF 26

Pharmacological comparison of human homomeric 5-HT3A receptors versus heteromeric 5-HT3A/3B receptors. Neuropharmacology. 2001 Aug;41(2):282-4.

REF 27

Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and... J Med Chem. 2010 Jun 10;53(11):4379-89.

REF 28

Allosteric interactions among agonists and antagonists at 5-hydroxytryptamine3 receptors. J Neurochem. 1995 Jul;65(1):104-10.

REF 29

Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5-HT3A receptors. Eur J Med Chem. 2009 Jun;44(6):2667-72.

REF 30

Aromatic thiazole derivatives: structurally novel and selective serotonin-3 receptor antagonists. J Med Chem. 1990 Jan;33(1):13-6.

REF 31

Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties. J Med Chem. 1994 Apr 29;37(9):1320-5.

REF 32

Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 2. Molecular basis of the intrinsic efficacy ... J Med Chem. 1999 May 6;42(9):1556-75.

REF 33

Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro. Eur J Pharmacol. 2000 Dec 8;409(2):195-201.

REF 34

Synthesis of heteroaromatic tropeines and heterogeneous binding to glycine receptors. Bioorg Med Chem. 2009 Oct 1;17(19):6872-8.

REF 35

Design and optimization of selective serotonin re-uptake inhibitors with high synthetic accessibility. Part 1. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2329-32.

REF 36

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 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.

REF 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 ag... J Med Chem. 2010 Feb 11;53(3):1222-37.

REF 38

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation. Bioorg Med Chem Lett. 2008 Jan 1;18(1):256-61.

REF 39

The 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 40

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... J Med Chem. 2008 Nov 27;51(22):7094-8.

REF 41

Binding sites for bilobalide, diltiazem, ginkgolide, and picrotoxinin at the 5-HT3 receptor. Mol Pharmacol. 2011 Jul;80(1):183-90.

REF 42

Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotoni... J Med Chem. 2003 Feb 27;46(5):702-15.

REF 43

Novel and highly potent 5-HT3 receptor agonists based on a pyrroloquinoxaline structure. J Med Chem. 1997 Oct 24;40(22):3670-8.

REF 44

Different 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 45

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:... Bioorg Med Chem Lett. 2008 Jun 15;18(12):3611-5.

REF 46

Novel, potent, and selective quinoxaline-based 5-HT(3) receptor ligands. 1. Further structure-activity relationships and pharmacological characteri... J Med Chem. 2009 Nov 12;52(21):6946-50.

REF 47

Characterization 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 48

Arginine 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.

REF 49

Autoradiographic distribution of [3H]-(S)-zacopride-labelled 5-HT3 receptors in human brain. J Neurol Sci. 1996 Dec;144(1-2):119-27.

REF 50

Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome. J Pharmacol Sci. 2007 Jul;104(3):263-73.

REF 51

Characterization 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 52

Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species. Mol Pharmacol. 1995 Sep;48(3):407-16.

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