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. 2009 Nov;158(Suppl 1):S11–S13. doi: 10.1111/j.1476-5381.2009.00501_3.x

5-HT (5-Hydroxytryptamine)

PMCID: PMC2884585

5-HT (5-Hydroxytryptamine) receptors [nomenclature as agreed by NC-IUPHAR Subcommittee on 5-HT receptors (Hoyer et al., 1994) and subsequently revised (Hartig et al., 1996)] are, with the exception of the ionotropic 5-HT3 class, 7TM receptors where the endogenous agonist is 5-HT. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique to the 7TM receptors, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology (reviewed by Bockaert et al., 2006; Werry et al., 2008).

Nomenclature 5-HT1A 5-HT1B 5-HT1D 5-ht1E
Other names – 5-HT1Dβ 5-HT1Dα –
Ensembl ID ENSG00000178394 ENSG00000135321 ENSG00000179546 ENSG00000168830
Principal transduction Gi/o Gi/o Gi/o Gi/o
Selective agonists (pKi) 8-OH-DPAT (8.4–9.4), U92016A (9.7) L694247 (9.2), CP94253 (8.7) PNU109291 (9.0 – gorilla, Ennis et al., 1998), sumatriptan (8.0–8.7), eletriptan (8.9), L694247 (9.0, Wurch et al., 1998) –
Selective antagonists (pKi) (±)WAY100635 (7.9–9.2), (S)-UH301 (7.9–8.6), NAD299 (robalzotan, 9.2) SB236057 (8.2, inverse agonist, Middlemiss et al., 1999), SB224289 (inverse agonist, 8.2–8.6), GR55562 (pKB 7.4, Hoyer et al., 2002) SB714786 (9.1) BRL15572 (7.9) –
Probes (KD) [3H]WAY100635 (0.3 nM, Khawaja et al., 1997), [3H]NAD299 (0.16 nM), [3H]8-OH-DPAT (0.4 nM), [11C]WAY100635 (PET ligand), p-[18F]MPPF (PET ligand) [3H]Alniditan (2.0–2.4 nM), [3H]eletriptan (3 nM), [3H]sumatriptan (11 nM) [125I]GTI, [3H]GR125743 (2.6 nM, Xie et al., 1999), [N-methyl-3H3]AZ10419369 (PET ligand) [3H]Alniditan (1.2–1.4 nM), [3H]eletriptan (0.9 nM), [3H]sumatriptan (7 nM), [125I]GTI, [3H]GR125743 (2.8 nM, Xie et al., 1999) [3H]5-HT (6 nM)
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Nomenclature 5-HT1F 5-HT2A 5-HT2B 5-HT2C
Other names 5-HT1Eβ, 5-HT6 D, 5-HT2 5-HT2F 5-HT1C
Ensembl ID ENSG00000179097 ENSG00000102468 ENSG00000135914 ENSG00000147246
Principal transduction Gi/o Gq/11 Gq/11 Gq/11
Selective agonists (pKi) LY344864 (8.2, Phebus et al et al., 1997) LY334370 (8.7) DOI (7.4–9.2) DOI (7.6–7.7), Ro600175 (8.3), BW723C86 (7.3–8.6) DOI (7.2–8.6), Ro600175 (7.7–8.2), WAY163909 (8.0, Dunlop et al., 2005), Locaserine (7.8, Thomsen et al., 2008)
Selective antagonists (pKi) – ketanserin (8.1–9.7), MDL100907 (9.4) RS127445 (9.0), EGIS-7625 (9.0) SB242084 (8.2–9.0), RS102221 (8.3–8.4), FR260010 (8.9, Harada et al., 2006)
Probes (KD) [3H]LY334370 (0.5 nM), [125I]LSD [3H]ketanserin (0.2–1.3 nM), [3H]RP62203 (fananserin, 0.13 nM – rat, Malgouris et al., 1993), [11C]M100907 (PET ligand), [18F]altanserin (PET ligand) [3H]5-HT (8 nM – rat) [3H]mesulergine (0.5–2.2 nM), [3H]LSD
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Nomenclature 5-HT4 5-ht5A 5-ht5B 5-HT6
Other names – 5-HT5α – –
Ensembl ID ENSG00000164270 ENSG00000157219 ENSMUSG00000050534 ENSG00000158748
Principal transduction Gs Gi/Go? None identified Gs
Selective agonists (pKi) BIMU8 (7.3), ML10302 (7.9–9.0), RS67506 (8.8 – guinea-pig, Eglen et al., 1995) – – WAY-181187 (8.7, Schechter et al., 2008)E-6801 (partial agonist, 8.7, Holenz et al., 2005)
Selective antagonists (pKi) GR113808 (9.3–10.3), SB204070 (9.8–10.4), RS100235 (8.7–12.2) SB699551 (8.2) – SB399886 (9.4, Hirst et al., 2006)SB271046 (8.9), SB357134 (8.5, Bromidge et al., 2001), Ro630563 (7.9–8.4)
Probes (KD) [3H]GR113808 (50–200 pM), [125I]SB207710 (86 pM – piglet, Brown et al., 1993), [3H]RS57639 (0.25 nM – guinea-pig, Bonhaus et al., 1997)[11C] SB207145 (PET ligand) [3H]5-CT (2.5 nM), [125I]LSD (0.2 nM) [3H]5-CT, [125I]LSD [125I]SB258585 (1.0 nM, Hirst et al., 2000), [3H]Ro630563 (5 nM, Boess et al., 1998), [3H]5-CT, [125I]LSD (2 nM)
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Nomenclature 5-HT7
Other names 5-HTX, 5-HT1-like
Ensembl ID ENSG00000148680
Principal transduction Gs
Selective agonists –
Selective antagonists (pKi) SB656104 (8.7, Forbes et al., 2002), SB269970 (8.6–8.9 Thomas et al., 2000), SB258719 (7.5)
Radioligands (KD) [3H]SB269970 (1.2 nM, Thomas et al., 2000), [3H]5-CT (0.4 nM, Thomas et al., 2000) [3H]LSD (3 nM), [3H]5-HT (1–8 nM)
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Tabulated pKi and KD values refer to binding to human 5-HT receptors unless indicated otherwise. Unreferenced values are extracted from the NC-IUPHAR database (http://www.iuphar-db.org). The nomenclature of 5-HT1B/5-HT1D receptors has been revised (Hartig et al., 1996). Only the non-rodent form of the receptor was previously called 5-HT1Dβ: the human 5-HT1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors. NAS181 is a selective antagonist of the rodent 5-HT1B receptor. Fananserin and ketanserin bind with high affinity to dopamine D4 and histamine H1 receptors respectively, in addition to 5-HT2A receptors. The human 5-ht5A receptor has been claimed to couple to several signal transduction pathways when stably expressed in C6 glioma cells (Noda et al., 2003). The human orthologue of the mouse 5-ht5B receptor is non-functional due to interruption of the gene by stop codons. In addition to the receptors listed in the table, an ‘orphan’ receptor, unofficially termed 5-HT1P, has been described (Gershon, 1999).

Glossary

Abbreviations:

5-CT

5-carboxamidotryptamine

8-OH-DPAT

8-hydroxy-2-(di-n-propylamino)tetralin

[N-methyl-3H3]AZ10419369

5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylicacid (4-morpholin-4-yl-phenyl)-amide

BIMU8

(endo-N-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide hydrochloride

BRL15572

3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1,-diphenyl-2-propanol

BW723C86

1-[5(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride

CP94253:

3- (1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3, 2-b] pyridine

E-6801

6-chloro-N-(3-(2-dimethylamino)ethyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide

EGIS-7625

1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine

FR260010

(N-[3-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6-dihydrobenzo[h]quinazolin-4-amine

GR55562

3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide

GR113808

[1-2[(methylsuphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate

GR125743

n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-3-methyl-4-(4-pyrindinyl)benzamide

GTI

5-hydroxytryptamine-5-O-carboxymethylglycyltyrosinamide

L694247

2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3yl] ethanamine

LY334370

5-(4-flurobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate

LY344864

N-[(6R)-6-dimethylamino-6,7,8,9-tetrahydro-5H-carbazo-3-yl]-4-fluorobenzamide

MDL100907

(+/-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]

NAD299

(R)-3-N,N-dicyclobutylamino-8-fluoro-[6-3H]-3,4-dihydro-2H-1-benzo pyran-5-carboxamide

NAS181

(R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methane sulfonate

p-[18F]MPPF

4-(2′-methoxyphenyl)-1-[2′-(N-2"-pyridinyl)-p-fluorobenzamido]-ethyl piperazine

PNU109291

(S)-3,4-dihydro-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-1H-2-benzopyran-6-carboximide

Ro600175

(S)-2-(6-chloro-5-fluroindol-1-yl)-1-methyethylamine

Ro630563

4-amino-N-[2,6-bis(methylamino)pyridin-4-yl]benzenesulphonamide

RP62203

2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8- ca]isothiazole-1,1-dioxide

RS57639

4-amino-5-chloro-2-methoxy benzoic acid 1-(3-[2,3-dihydrobenzo[1,4]dioxin-6yl)-propyl]-piperidin-4yl methyl ester

RS67506

1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride

RS100235

1-(8-amino-7-chloro-1,4-benzodioxan-5-yl)-5-((3-(3,4-dimethoxyphenyl)prop-1-yl)piperidin-4-yl)propan-1-one

RS102221

8-[5-(5-amino 2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione

RS127445

(2-amino-4-(4-fluoronaphthyl-1-yl)-6-isopropylpyrimidine)

SB204070

1-butyl-4-piperidinylmethyl-8-amino-7-chloro-1-4-benzoioxan-5-carboxylate

SB207710

1-butyl-4-piperidinylmethyl-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate

SB224289

1′-methyl-5[[2′-methyl-4′-)5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4′-piperidine]oxalate

SB236057

1′-ethyl-5-(2′-methyl-4′-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indol3-3,4′-piperidine

SB242084

6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline

SB258585

4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulphonamide

SB258719

(R)-3,N-dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulphonamide

SB269970

(R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulphonyl)phenol

SB271046

5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulphonamide

SB357134

N-(2,5-dibromo-3-flurophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulphonamide

SB-399885

N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide

SB656104

6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride

SB699551

3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride

SB714786

2-methyl-5-({2-[4-(8-quinolinylmethyl)-1-piperazinyl]ethyl}oxy)quinoline

U92016A

(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole

UH301

5-fluoro-8-hydroxy-2-(dipropylamino) tetralin

WAY100635

N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexanecarboxamide trichloride

WAY163909

(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole

WAY-181187

2-[1-(6-chloroimidazo[2,1-b]thiazol-5-ylsulfonyl)-1H-indol-3-yl]ethylamine

Further Reading

Barnes NM, Sharp T (1999). A review of central 5-HT receptors and their function. Neuropharmacology38: 1083–1152.

Bockaert J, Claeysen S, Becamel C, Dumuis A, Marin P (2006). Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res326: 553–572.

Bockaert J, Claeysen S, Compan V, Dumuis A (2008). 5-HT4 receptors: history, molecular pharmacology and brain functions. Neuropharmacology55: 922–931.

Bojarski AJ (2006). Pharmacophore models for metabotropic 5-HT receptor ligands. Curr Top Med Chem 6:2005–2026.

Bonasera SJ, Tecott LH (2000). Mouse models of serotonin receptor function: toward a genetic dissection of serotonin systems. Pharmacol Ther88: 133–142.

Caliendo G, Santagada V, Perissutti E, Fiorino F. (2005). Derivatives as 5HT1A receptor ligands – past and present. Curr Med Chem12: 1721–1753.

Fink KB, Göthert M (2007). 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev59: 360–417.

Gershon MD (1999). Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther 13 (Suppl. 2): 15–30.

Glennon RA (2003). Higher-end serotonin receptors: 5-HT5, 5-HT6, and 5-HT7. J Med Chem46: 2795–812.

Hartig PR, Hoyer D, Humphrey PP, Martin GR (1996). Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol Sci17: 103–105.

Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (2008). Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders. Pharmacol Ther117: 207–231.

Hoyer D, Martin G (1997). 5-HT receptor classification and nomenclature: towards a harmonization with the human genome Neuropharmacology36: 419–428.

Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ et al. (1994). International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev46: 157–203.

Hoyer D, Hannon JP, Martin GR (2002). Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav71: 533–554.

King MV, Marsden CA, Fone KC (2008). A role for the 5-HT1A, 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol Sci29: 482–492.

Kitson SL (2007). 5-hydroxytryptamine (5-HT) receptor ligands. Curr Pharm Des13: 2621–2637.

Lanfumey L, Hamon M (2004). 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord3: 1–10.

Leysen JE (2004). 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord3: 11–26.

Nelson DL (2004). 5-HT5 receptors. Curr Drug Targets CNS Neurol Disord3: 53–58.

Pauwels PJ (2000). Diverse signalling by 5-hydroxytryptamine (5-HT) receptors. Biochem Pharmacol60: 1743–1750.

Ramage AG, Villalón CM (2008). 5-Hydroxytryptamine and cardiovascular regulation. Trends Pharmacol Sci29: 472–481

Sanger GJ (2008). 5-hydroxytryptamine and the gastrointestinal tract: where next? Trends Pharmacol Sci29: 465–471.

Thomas DR (2006). 5-ht5A receptors as a therapeutic target. Pharmacol Ther111: 707–714.

Thomas DR, Hagan JJ (2004). 5-HT7 receptors. Curr Drug Targets CNS Neurol Disord3: 81–90.

Villalón CM, Centurión D (2007). Cardiovascular responses produced by 5-hydroxytryptamine: a pharmacological update on the receptors/mechanisms involved and therapeutic implications. Naunyn Schmiedebergs Arch Pharmacol376: 45–63.

Werry TD, Loiacono R, Sexton PM, Christopoulos A (2008). RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function. Pharmacol Ther119: 7–23.

Woolley ML, Marsden CA, Fone KC (2004). 5-ht6 receptors. Curr Drug Targets CNS Neurol Disord3: 59–79.

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