5-HT6 receptor

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5-hydroxytryptamine (serotonin) receptor 6, G protein-coupled
Symbols HTR6 ; 5-HT6; 5-HT6R
External IDs OMIM601109 MGI1196627 HomoloGene673 IUPHAR: 11 ChEMBL: 3371 GeneCards: HTR6 Gene
RNA expression pattern
PBB GE HTR6 206944 at tn.png
More reference expression data
Species Human Mouse
Entrez 3362 15565
Ensembl ENSG00000158748 ENSMUSG00000028747
UniProt P50406 Q9R1C8
RefSeq (mRNA) NM_000871 NM_021358
RefSeq (protein) NP_000862 NP_067333
Location (UCSC) Chr 1:
19.67 – 19.68 Mb
Chr 4:
139.06 – 139.08 Mb
PubMed search [1] [2]

The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).[1] It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission.[1] HTR6 denotes the human gene encoding for the receptor.[2]


The 5-HT6 receptor is expressed almost exclusively in the brain.[3] It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum.[1][4][5] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[3][5][6]


Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[7][8][9][10] whereas activation enhances GABAergic signaling in a widespread manner.[11] Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[10][12] while stimulation has the opposite effect.[11]

Despite the 5-HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[11] In parallel with this, 5-HT6 antagonists improve cognition, learning, and memory,[13] and agents such as latrepirdine, idalopirdine (Lu AE58054), and SB-742,457 are being developed as novel treatments for Alzheimer's disease and other forms of dementia.[10][14][15] 5-HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.[16][17]

Recently, the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.[11][18] Additionally, indirect 5-HT6 activation may play a role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).[citation needed]


A large number of selective 5-HT6 ligands have now been developed and this is a productive current area of research.[19][20][21][22][23][24][25]

Full agonists[edit]

Partial Agonists[edit]

  • E-6801[30]
  • E-6837 - partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration[31]
  • LSD - Emax = 60%[32]



Polymorphisms in the HTR6 gene are associated with neuropsychiatric disorders. For example an association between the C267T (rs1805054) polymorphism and Alzheimer's disease has been shown.[37] Others have studied the polymorphism in relation to Parkinson's disease.[38]

See also[edit]


  1. ^ a b c Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (Jan 1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". Journal of Neurochemistry 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988. 
  2. ^ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6". 
  3. ^ a b Woolley ML, Marsden CA, Fone KC (Feb 2004). "5-HT6 receptors". Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79. doi:10.2174/1568007043482561. PMID 14965245. 
  4. ^ Ruat M, Traiffort E, Arrang JM, Tardivel-Lacombe J, Diaz J, Leurs R, Schwartz JC (May 1993). "A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation". Biochemical and Biophysical Research Communications 193 (1): 268–76. doi:10.1006/bbrc.1993.1619. PMID 8389146. 
  5. ^ a b Gérard C, Martres MP, Lefèvre K, Miquel MC, Vergé D, Lanfumey L, Doucet E, Hamon M, el Mestikawy S (Jan 1997). "Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system". Brain Research 746 (1-2): 207–19. doi:10.1016/S0006-8993(96)01224-3. PMID 9037500. 
  6. ^ Hamon M, Doucet E, Lefèvre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Vergé D (Aug 1999). "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors". Neuropsychopharmacology 21 (2 Suppl): 68S–76S. doi:10.1016/S0893-133X(99)00044-5. PMID 10432491. 
  7. ^ Dawson LA, Nguyen HQ, Li P (May 2000). "In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate". British Journal of Pharmacology 130 (1): 23–6. doi:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993. 
  8. ^ Dawson LA, Nguyen HQ, Li P (Nov 2001). "The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus". Neuropsychopharmacology 25 (5): 662–8. doi:10.1016/S0893-133X(01)00265-2. PMID 11682249. 
  9. ^ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (Aug 2004). "5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism". Neuropharmacology 47 (2): 195–204. doi:10.1016/j.neuropharm.2004.03.012. PMID 15223298. 
  10. ^ a b c Upton N, Chuang TT, Hunter AJ, Virley DJ (Jul 2008). "5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease". Neurotherapeutics 5 (3): 458–69. doi:10.1016/j.nurt.2008.05.008. PMID 18625457. 
  11. ^ a b c d e f Schechter LE, Lin Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE (May 2008). "Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466". Neuropsychopharmacology 33 (6): 1323–35. doi:10.1038/sj.npp.1301503. PMID 17625499. 
  12. ^ Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (Feb 2004). "5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex". Synapse 51 (2): 158–64. doi:10.1002/syn.10288. PMID 14618683. 
  13. ^ King MV, Marsden CA, Fone KC (Sep 2008). "A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory". Trends in Pharmacological Sciences 29 (9): 482–92. doi:10.1016/j.tips.2008.07.001. PMID 19086256. 
  14. ^ Geldenhuys WJ, Van der Schyf CJ (2008). "Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease". Current Topics in Medicinal Chemistry 8 (12): 1035–48. doi:10.2174/156802608785161420. PMID 18691131. 
  15. ^ Geldenhuys WJ, Van der Schyf CJ (Jul 2009). "The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease". Expert Review of Neurotherapeutics 9 (7): 1073–85. doi:10.1586/ern.09.51. PMID 19589055. 
  16. ^ a b Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (Feb 2008). "Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders". Pharmacology & Therapeutics 117 (2): 207–31. doi:10.1016/j.pharmthera.2007.08.006. PMID 18068807. 
  17. ^ Frassetto A, Zhang J, Lao JZ, White A, Metzger JM, Fong TM, Chen RZ (Oct 2008). "Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor". Brain Research 1236: 140–4. doi:10.1016/j.brainres.2008.08.012. PMID 18755168. 
  18. ^ Carr GV, Schechter LE, Lucki I (Feb 2011). "Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats". Psychopharmacology 213 (2-3): 499–507. doi:10.1007/s00213-010-1798-7. PMC 2910165. PMID 20217056. 
  19. ^ Trani G, Baddeley SM, Briggs MA, Chuang TT, Deeks NJ, Johnson CN, Khazragi AA, Mead TL, Medhurst AD, Milner PH, Quinn LP, Ray AM, Rivers DA, Stean TO, Stemp G, Trail BK, Witty DR (Oct 2008). "Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 18 (20): 5698–700. doi:10.1016/j.bmcl.2008.08.010. PMID 18793848. 
  20. ^ Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith DL, Di L, Kerns EH, Schechter LE, Robichaud AJ (Feb 2009). "Identification of a series of benzoxazoles as potent 5-HT6 ligands". Bioorganic & Medicinal Chemistry Letters 19 (4): 1115–7. doi:10.1016/j.bmcl.2008.12.107. PMID 19152787. 
  21. ^ Lee M, Rangisetty JB, Pullagurla MR, Dukat M, Setola V, Roth BL, Glennon RA (Mar 2005). "1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands". Bioorganic & Medicinal Chemistry Letters 15 (6): 1707–11. doi:10.1016/j.bmcl.2005.01.031. PMID 15745826. 
  22. ^ Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (Aug 2006). "Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors". Journal of Medicinal Chemistry 49 (17): 5217–25. doi:10.1021/jm060469q. PMID 16913710. 
  23. ^ Zhou P, Yan Y, Bernotas R, Harrison BL, Huryn D, Robichaud AJ, Zhang GM, Smith DL, Schechter LE (Mar 2005). "4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands". Bioorganic & Medicinal Chemistry Letters 15 (5): 1393–6. doi:10.1016/j.bmcl.2005.01.005. PMID 15713394. 
  24. ^ Ahmed M, Briggs MA, Bromidge SM, Buck T, Campbell L, Deeks NJ, Garner A, Gordon L, Hamprecht DW, Holland V, Johnson CN, Medhurst AD, Mitchell DJ, Moss SF, Powles J, Seal JT, Stean TO, Stemp G, Thompson M, Trail B, Upton N, Winborn K, Witty DR (Nov 2005). "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 15 (21): 4867–71. doi:10.1016/j.bmcl.2005.06.107. PMID 16143522. 
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  26. ^ Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Böttcher H (Oct 2005). "2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists". Bioorganic & Medicinal Chemistry Letters 15 (19): 4230–4. doi:10.1016/j.bmcl.2005.06.067. PMID 16055331. 
  27. ^ Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (Mar 2000). "2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors". Journal of Medicinal Chemistry 43 (5): 1011–8. doi:10.1021/jm990550b. PMID 10715164. 
  28. ^ Cole DC, Stock JR, Lennox WJ, Bernotas RC, Ellingboe JW, Boikess S, Coupet J, Smith DL, Leung L, Zhang GM, Feng X, Kelly MF, Galante R, Huang P, Dawson LA, Marquis K, Rosenzweig-Lipson S, Beyer CE, Schechter LE (Nov 2007). "Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist". Journal of Medicinal Chemistry 50 (23): 5535–8. doi:10.1021/jm070521y. PMID 17948978. 
  29. ^ Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (Feb 2009). "Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists". Journal of Medicinal Chemistry 52 (3): 675–87. doi:10.1021/jm8009469. PMID 19159187. 
  30. ^ Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (Aug 2006). "Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways". British Journal of Pharmacology 148 (8): 1133–43. doi:10.1038/sj.bjp.0706827. PMC 1752021. PMID 16865095. 
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  32. ^ Boess FG, Monsma FJ, Carolo C, Meyer V, Rudler A, Zwingelstein C, Sleight AJ (1997). "Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells". Neuropharmacology 36 (4-5): 713–20. doi:10.1016/s0028-3908(97)00019-1. PMID 9225298. 
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Further reading[edit]

  • Hoyer D, Hannon JP, Martin GR (Apr 2002). "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacology, Biochemistry, and Behavior 71 (4): 533–54. doi:10.1016/S0091-3057(01)00746-8. PMID 11888546. 
  • Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacology & Therapeutics 92 (2-3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537. 
  • Van Oekelen D, Luyten WH, Leysen JE (Apr 2003). "5-HT2A and 5-HT2C receptors and their atypical regulation properties". Life Sciences 72 (22): 2429–49. doi:10.1016/S0024-3205(03)00141-3. PMID 12650852. 
  • Dubertret C, Hanoun N, Adès J, Hamon M, Gorwood P (Apr 2004). "Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 126B (1): 10–5. doi:10.1002/ajmg.b.20120. PMID 15048641. 
  • Ullmer C, Schmuck K, Kalkman HO, Lübbert H (Aug 1995). "Expression of serotonin receptor mRNAs in blood vessels". FEBS Letters 370 (3): 215–21. doi:10.1016/0014-5793(95)00828-W. PMID 7656980. 
  • Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (Jan 1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". Journal of Neurochemistry 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988. 
  • Orlacchio A, Kawarai T, Paciotti E, Stefani A, Orlacchio A, Sorbi S, St George-Hyslop PH, Bernardi G (May 2002). "Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease". Neuroscience Letters 325 (1): 13–6. doi:10.1016/S0304-3940(02)00221-5. PMID 12023056. 
  • Ham BJ, Kim YH, Choi MJ, Cha JH, Choi YK, Lee MS (Jan 2004). "Serotonergic genes and personality traits in the Korean population". Neuroscience Letters 354 (1): 2–5. doi:10.1016/S0304-3940(03)00753-5. PMID 14698468. 
  • Bernotas R, Lenicek S, Antane S, Zhang GM, Smith D, Coupet J, Harrison B, Schechter LE (Nov 2004). "1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands". Bioorganic & Medicinal Chemistry Letters 14 (22): 5499–502. doi:10.1016/j.bmcl.2004.09.003. PMID 15482912. 
  • Kang H, Lee WK, Choi YH, Vukoti KM, Bang WG, Yu YG (Apr 2005). "Molecular analysis of the interaction between the intracellular loops of the human serotonin receptor type 6 (5-HT6) and the alpha subunit of GS protein". Biochemical and Biophysical Research Communications 329 (2): 684–92. doi:10.1016/j.bbrc.2005.02.040. PMID 15737640. 
  • Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R (Aug 2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods 2 (8): 591–8. doi:10.1038/nmeth776. PMID 16094384. 
  • Lorke DE, Lu G, Cho E, Yew DT (2006). "Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients". BMC Neuroscience 7: 36. doi:10.1186/1471-2202-7-36. PMC 1523198. PMID 16640790. 
  • Yun HM, Kim S, Kim HJ, Kostenis E, Kim JI, Seong JY, Baik JH, Rhim H (Feb 2007). "The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn". The Journal of Biological Chemistry 282 (8): 5496–505. doi:10.1074/jbc.M606215200. PMID 17189269. 

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.