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5-HT6 receptor

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HTR6
Identifiers
AliasesHTR6, 5-HT6, 5-HT6R, 5-HT6 receptor, 5-hydroxytryptamine receptor 6
External IDsOMIM: 601109; MGI: 1196627; HomoloGene: 673; GeneCards: HTR6; OMA:HTR6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3362

15565

Ensembl

ENSG00000158748

ENSMUSG00000028747

UniProt

P50406

Q9R1C8

RefSeq (mRNA)

NM_000871

NM_021358
NM_001377096

RefSeq (protein)

NP_000862

NP_067333
NP_001364025

Location (UCSC)Chr 1: 19.66 – 19.68 MbChr 4: 138.79 – 138.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT).[5] It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission.[5] HTR6 denotes the human gene encoding for the receptor.[6]

Distribution

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The 5HT6 receptor is expressed almost exclusively in the brain.[7] 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.[5][8][9] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[7][9][10]

Function

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Blockade of central 5HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[11][12][13][14] whereas activation enhances GABAergic signaling in a widespread manner.[15] Antagonism of 5HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[14][16] while stimulation has the opposite effect.[15]

As a drug target for antagonists

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Despite the 5HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[15] In parallel with this, 5HT6 antagonists are hypothesized to improve cognition, learning, and memory.[17] Agents such as latrepirdine, idalopirdine (Lu AE58054), and intepirdine (SB-742,457/RVT-101) were evaluated as novel treatments for Alzheimer's disease and other forms of dementia.[14][18][19] However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

5HT6 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.[20][21]

As a drug target for agonists

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Recently, the 5HT6 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.[15][22] Additionally, indirect 5HT6 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]

Ligands

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A large number of selective 5HT6 ligands have now been developed.[23][24][25][26][27][28][29][30][31]

Agonists

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Full agonists

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Partial agonists

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  • E-6801[34]
  • E-6837 – partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration[35]
  • EMD-386,088 – potent partial agonist (EC50 = 1 nM) but non-selective[36][37]
  • LSD – Emax = 60%[38]

Antagonists and inverse agonists

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Genetics

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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.[45] Others have studied the polymorphism in relation to Parkinson's disease.[46]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000158748 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028747 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (January 1996). "Cloning, characterization, and chromosomal localization of a human 5HT6 serotonin receptor". Journal of Neurochemistry. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988. S2CID 35874409.
  6. ^ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6".
  7. ^ a b Woolley ML, Marsden CA, Fone KC (February 2004). "5HT6 receptors". Current Drug Targets. CNS and Neurological Disorders. 3 (1): 59–79. doi:10.2174/1568007043482561. PMID 14965245.
  8. ^ 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.
  9. ^ a b Gérard C, Martres MP, Lefèvre K, Miquel MC, Vergé D, Lanfumey L, Doucet E, Hamon M, el Mestikawy S (January 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. S2CID 23364990.
  10. ^ Hamon M, Doucet E, Lefèvre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Vergé D (August 1999). "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5HT6 receptors". Neuropsychopharmacology. 21 (2 Suppl): 68S–76S. doi:10.1016/S0893-133X(99)00044-5. PMID 10432491.
  11. ^ Dawson LA, Nguyen HQ, Li P (May 2000). "In vivo effects of the 5HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5HT, glutamate and aspartate". British Journal of Pharmacology. 130 (1): 23–6. doi:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993.
  12. ^ Dawson LA, Nguyen HQ, Li P (November 2001). "The 5HT(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.
  13. ^ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (August 2004). "5HT6 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. S2CID 1736645.
  14. ^ a b c Upton N, Chuang TT, Hunter AJ, Virley DJ (July 2008). "5HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease". Neurotherapeutics. 5 (3): 458–69. doi:10.1016/j.nurt.2008.05.008. PMC 5084247. PMID 18625457.
  15. ^ a b c d 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.
  16. ^ 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. doi:10.1002/syn.10288. PMID 14618683. S2CID 6539467.
  17. ^ King MV, Marsden CA, Fone KC (September 2008). "A role for the 5HT(1A), 5HT4 and 5HT6 receptors in learning and memory". Trends in Pharmacological Sciences. 29 (9): 482–92. doi:10.1016/j.tips.2008.07.001. PMID 19086256.
  18. ^ Geldenhuys WJ, Van der Schyf CJ (2008). "Serotonin 5HT6 receptor antagonists for the treatment of Alzheimer's disease". Current Topics in Medicinal Chemistry. 8 (12): 1035–48. doi:10.2174/156802608785161420. PMID 18691131. Archived from the original on 14 April 2013.{{cite journal}}: CS1 maint: unfit URL (link)
  19. ^ 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. doi:10.1586/ern.09.51. PMID 19589055. S2CID 3066907.
  20. ^ 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. doi:10.1016/j.pharmthera.2007.08.006. PMID 18068807.
  21. ^ Frassetto A, Zhang J, Lao JZ, White A, Metzger JM, Fong TM, Chen RZ (October 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. S2CID 33355136.
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  23. ^ 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". Bioorganic & Medicinal Chemistry Letters. 18 (20): 5698–700. doi:10.1016/j.bmcl.2008.08.010. PMID 18793848.
  24. ^ 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". Bioorganic & Medicinal Chemistry Letters. 19 (4): 1115–7. doi:10.1016/j.bmcl.2008.12.107. PMID 19152787.
  25. ^ Lee M, Rangisetty JB, Pullagurla MR, Dukat M, Setola V, Roth BL, Glennon RA (March 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.
  26. ^ Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (August 2006). "Binding of sulfonyl-containing arylalkylamines at human 5HT6 serotonin receptors". Journal of Medicinal Chemistry. 49 (17): 5217–25. doi:10.1021/jm060469q. PMID 16913710.
  27. ^ Benhamú B, Martín-Fontecha M, Vázquez-Villa H, Pardo L, López-Rodríguez ML (2014). "Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease". J. Med. Chem. 57 (17): 7160–81. doi:10.1021/jm5003952. PMID 24850589.
  28. ^ van Loevezijn A, Venhorst J, Iwema Bakker WI, Lange JH, de Looff W, Henzen R, de Vries J, van de Woestijne RP, den Hartog AP, Verhoog S, van der Neut MA, de Bruin NM, Kruse CG (2016). "Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket". Bioorg. Med. Chem. Lett. 26 (6): 1605–11. doi:10.1016/j.bmcl.2016.02.001. PMID 26876931.
  29. ^ 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 (November 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.
  30. ^ Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (October 2008). "Indene-based scaffolds. Design and synthesis of novel serotonin 5HT6 receptor ligands". Organic & Biomolecular Chemistry. 6 (20): 3795–810. doi:10.1039/b808641a. PMID 18843410.
  31. ^ Zhou P, Yan Y, Bernotas R, Harrison BL, Huryn D, Robichaud AJ, Zhang GM, Smith DL, Schechter LE (March 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.
  32. ^ Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (March 2000). "2-Substituted tryptamines: agents with selectivity for 5HT(6) serotonin receptors". Journal of Medicinal Chemistry. 43 (5): 1011–8. doi:10.1021/jm990550b. PMID 10715164.
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  34. ^ Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (August 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.
  35. ^ 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). "Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats". British Journal of Pharmacology. 148 (7): 973–83. doi:10.1038/sj.bjp.0706807. PMC 1751931. PMID 16783408.
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Further reading

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

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