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5-HT6 receptor

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Title: 5-HT6 receptor  
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Subject: 5-HT1 receptor, 5-HT5A receptor, Blonanserin, 5-HT4 receptor, 5-HT7 receptor
Collection: G Protein Coupled Receptors, Human Proteins
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5-HT6 receptor

5-hydroxytryptamine (serotonin) receptor 6, G protein-coupled
Symbols  ; 5-HT6; 5-HT6R
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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]


  • Distribution 1
  • Function 2
  • Ligands 3
    • Full agonists 3.1
    • Partial Agonists 3.2
    • Antagonists 3.3
  • Genetics 4
  • See also 5
  • References 6
  • Further reading 7
  • External links 8


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, 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, it can be inferred that 5-HT6 activation likely plays a major role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).


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

Partial Agonists

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



The receptor is encoded by the HTR6 gene. As the protein is a neuroreceptor it is possible that genetic variations in the gene would have an effect on brain, and research studies have investigated whether polymorphisms is associated with brain-related variables, such as neuropsychiatric disorders. For example, in 2004 one Chinese study reported an association between the C267T (rs1805054) polymorphism and Alzheimer's disease.[36] Others have studied the polymorphism in relation to Parkinson's disease.[37]

See also


  1. ^ a b c Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". J. Neurochem. 66 (1): 47–56.  
  2. ^ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6". 
  3. ^ a b Woolley ML, Marsden CA, Fone KC (February 2004). "5-ht6 receptors". Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79.  
  4. ^ Ruat M, Traiffort E, Arrang JM, et al. (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.  
  5. ^ a b Gérard C, Martres MP, Lefèvre K, et al. (January 1997). "Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system". Brain Research 746 (1-2): 207–19.  
  6. ^ Hamon M, Doucet E, Lefèvre K, et al. (August 1999). "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors". Neuropsychopharmacology 21 (2 Suppl): 68S–76S.  
  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.  
  8. ^ Dawson LA, Nguyen HQ, Li P (November 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.  
  9. ^ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (August 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.  
  10. ^ a b c Upton N, Chuang TT, Hunter AJ, Virley DJ (July 2008). "5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease". Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 5 (3): 458–69.  
  11. ^ a b c d e f Schechter LE, Lin Q, Smith DL, et al. (May 2008). "Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466". Neuropsychopharmacology 33 (6): 1323–35.  
  12. ^ Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (February 2004). "5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex". Synapse 51 (2): 158–64.  
  13. ^ King MV, Marsden CA, Fone KC (September 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.  
  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.  
  15. ^ Geldenhuys WJ, Van der Schyf CJ (July 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.  
  16. ^ a b Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (February 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.  
  17. ^ Frassetto A, Zhang J, Lao JZ, et al. (October 2008). "Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor". Brain Research 1236: 140–4.  
  18. ^ Carr GV, Schechter LE, Lucki I (March 2010). "Antidepressant and anxiolytic effects of selective 5-HT(6) receptor agonists in rats". Psychopharmacology 213 (2-3): 499–507.  
  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 (October 2008). "Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists". Bioorg. Med. Chem. Lett. 18 (20): 5698–700.  
  20. ^ Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith DL, Di L, Kerns EH, Schechter LE, Robichaud AJ (February 2009). "Identification of a series of benzoxazoles as potent 5-HT6 ligands". Bioorg. Med. Chem. Lett. 19 (4): 1115–7.  
  21. ^ Lee M, Rangisetty JB, Pullagurla MR, et al (2005). "1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands". Bioorg. Med. Chem. Lett. 15 (6): 1707–11.  
  22. ^ Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (2006). "Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors". J. Med. Chem. 49 (17): 5217–25.  
  23. ^ Zhou P, Yan Y, Bernotas R, et al (2005). "4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands". Bioorg. Med. Chem. Lett. 15 (5): 1393–6.  
  24. ^ Ahmed M, Briggs MA, Bromidge SM, et al (2005). "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists". Bioorg. Med. Chem. Lett. 15 (21): 4867–71.  
  25. ^ Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (October 2008). "Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6 receptor ligands". Org. Biomol. Chem. 6 (20): 3795–810.  
  26. ^ Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Böttcher H (October 2005). "2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists". Bioorg. Med. Chem. Lett. 15 (19): 4230–4.  
  27. ^ Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (2000). "2-Substituted tryptamines: agents with selectivity for 5-HT6 serotonin receptors". J. Med. Chem. 43 (5): 1011–8.  
  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 (November 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.  
  29. ^ Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (2009). "Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists". J. Med. Chem. 52 (3): 675–87.  
  30. ^ Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (August 2006). receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways"6"Efficacy of selective 5-HT. Br. J. Pharmacol. 148 (8): 1133–43.  
  31. ^ Fisas A, Codony X, Romero G, Dordal A, Giraldo J, Mercé R, Holenz J, Vrang N, Sørensen RV, Heal D, Buschmann H, Pauwels PJ (August 2006). receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats"6"Chronic 5-HT. Br. J. Pharmacol. 148 (7): 973–83.  
  32. ^ Hugerth A, Brisander M, Wrange U, Kritikos M, Norrlind B, Svensson M, Bisrat M, Ostelius J (February 2006). "Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT6 receptor antagonist". Drug Dev Ind Pharm 32 (2): 185–96.  
  33. ^ Wu, J; Li, Q; Bezprozvanny, I (2008). "Evaluation of Dimebon in cellular model of Huntington's disease.". Molecular neurodegeneration 3: 15.  
  34. ^ Ivachtchenko AV, Frolov EB, Mitkin OD, Kysil VM, Khvat AV, Okun IM, Tkachenko SE (June 2009). "Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 19 (12): 3183–7.  
  35. ^ Liu KG, Robichaud AJ, Bernotas RC, et al. (November 2010). "5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists". J. Med. Chem. 53 (21): 7639–46.  
  36. ^ Kan R, Wang B, Zhang C, Yang Z, Ji S, Lu Z, Zheng C, Jin F, Wang L (November 2004). "Association of the HTR6 polymorphism C267T with late-onset Alzheimer's disease in Chinese". Neurosci. Lett. 372 (1-2): 27–9.  
  37. ^ Messina D, Annesi G, Serra P, Nicoletti G, Pasqua A, Annesi F, Tomaino C, Cirò-Candiano IC, Carrideo S, Caracciolo M, Spadafora P, Zappia M, Savettieri G, Quattrone A (12 March 2002). "Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease". Neurology 58 (5): 828–9.  

Further reading

  • Hoyer D, Hannon JP, Martin GR (2002). "Molecular, pharmacological and functional diversity of 5-HT receptors.". Pharmacol. Biochem. Behav. 71 (4): 533–54.  
  • Raymond JR, Mukhin YV, Gelasco A, et al. (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction.". Pharmacol. Ther. 92 (2-3): 179–212.  
  • Van Oekelen D, Luyten WH, Leysen JE (2003). "5-HT2A and 5-HT2C receptors and their atypical regulation properties.". Life Sci. 72 (22): 2429–49.  
  • Dubertret C, Hanoun N, Adès J, et al. (2004). "Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia.". Am. J. Med. Genet. B Neuropsychiatr. Genet. 126 (1): 10–5.  
  • Ullmer C, Schmuck K, Kalkman HO, Lübbert H (1995). "Expression of serotonin receptor mRNAs in blood vessels.". FEBS Lett. 370 (3): 215–21.  
  • Kohen R, Metcalf MA, Khan N, et al. (1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor.". J. Neurochem. 66 (1): 47–56.  
  • Orlacchio A, Kawarai T, Paciotti E, et al. (2002). "Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease.". Neurosci. Lett. 325 (1): 13–6.  
  • Mammalian Gene Collection Program Team; Strausberg, R. L.; Feingold, E. A.; Grouse, L. H. et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences".  
  • Ham BJ, Kim YH, Choi MJ, et al. (2004). "Serotonergic genes and personality traits in the Korean population.". Neurosci. Lett. 354 (1): 2–5.  
  • Bernotas R, Lenicek S, Antane S, et al. (2005). "1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands.". Bioorg. Med. Chem. Lett. 14 (22): 5499–502.  
  • Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7.  
  • Kang H, Lee WK, Choi YH, et al. (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.". Biochem. Biophys. Res. Commun. 329 (2): 684–92.  
  • Tao WA, Wollscheid B, O'Brien R, et al. (2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry.". Nat. Methods 2 (8): 591–8.  
  • 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.  
  • Yun HM, Kim S, Kim HJ, et al. (2007). "The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn.". J. Biol. Chem. 282 (8): 5496–505.  

External links

  • "6"5-HT. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 
  • serotonin 6 receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

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