5-HT6 receptor

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The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT).[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

The 5HT6 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 5HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[3][5][6]

Function

Blockade of central 5HT6 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 5HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[10][12] while stimulation has the opposite effect.[11]

As a drug target for antagonists

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.[11] In parallel with this, 5HT6 antagonists are hypothesized to improve cognition, learning, and memory.[13] 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.[10][14][15] 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.[16][17]

As a drug target for agonists

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.[11][18] 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

A large number of selective 5HT6 ligands have now been developed.[19][20][21][22][23][24][25][26][27]

Agonists

Full agonists

Partial agonists

Antagonists and inverse agonists

Genetics

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.[41] Others have studied the polymorphism in relation to Parkinson's disease.[42]

See also

References

  1. ↑ 1.0 1.1 1.2 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 5HT6 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. ↑ 3.0 3.1 Woolley ML, Marsden CA, Fone KC (Feb 2004). "5HT6 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. ↑ 5.0 5.1 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 5HT6 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 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.
  8. ↑ Dawson LA, Nguyen HQ, Li P (Nov 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.
  9. ↑ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (Aug 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.
  10. ↑ 10.0 10.1 10.2 Upton N, Chuang TT, Hunter AJ, Virley DJ (Jul 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. PMID 18625457.
  11. ↑ 11.0 11.1 11.2 11.3 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 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.
  14. ↑ 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.
  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. ↑ 16.0 16.1 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 5HT6 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 5HT6 serotonin receptors". Journal of Medicinal Chemistry. 49 (17): 5217–25. doi:10.1021/jm060469q. PMID 16913710.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (Oct 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.
  27. ↑ 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.
  28. ↑ 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 5HT(6) serotonin receptors". Journal of Medicinal Chemistry. 43 (5): 1011–8. doi:10.1021/jm990550b. PMID 10715164.
  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.
  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 (Aug 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.
  32. ↑ 32.0 32.1 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.
  33. ↑ Jastrzębska-Więsek M, Siwek A, Partyka A, Antkiewicz-Michaluk L, Michaluk J, Romańska I, Kołaczkowski M, Wesołowska A (2016). "Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT6 partial agonist in rats". Naunyn Schmiedebergs Arch. Pharmacol. 389: 839–49. doi:10.1007/s00210-016-1245-3. PMC 4939156. PMID 27106213.
  34. ↑ 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.
  35. ↑ Hugerth A, Brisander M, Wrange U, Kritikos M, Norrlind B, Svensson M, Bisrat M, Ostelius J (Feb 2006). "Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT(6) receptor antagonist". Drug Development and Industrial Pharmacy. 32 (2): 185–96. doi:10.1080/03639040500466122. PMID 16537199.
  36. ↑ Wu J, Li Q, Bezprozvanny I (2008). "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration. 3: 15. doi:10.1186/1750-1326-3-15. PMC 2577671. PMID 18939977.
  37. ↑ Ivachtchenko AV, Frolov EB, Mitkin OD, Kysil VM, Khvat AV, Okun IM, Tkachenko SE (Jun 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. doi:10.1016/j.bmcl.2009.04.128. PMID 19443217.
  38. ↑ Gravius A, Laszy J, Pietraszek M, Sághy K, Nagel J, Chambon C, Wegener N, Valastro B, Danysz W, Gyertyán I (2011). "Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity". Behav Pharmacol. 22 (2): 122–35. doi:10.1097/FBP.0b013e328343d804. PMID 21301322.
  39. ↑ Liu KG, Robichaud AJ, Bernotas RC, Yan Y, Lo JR, Zhang MY, Hughes ZA, Huselton C, Zhang GM, Zhang JY, Kowal DM, Smith DL, Schechter LE, Comery TA (Nov 2010). "5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists". Journal of Medicinal Chemistry. 53 (21): 7639–46. doi:10.1021/jm1007825. PMID 20932009.
  40. ↑ Na JR, Oh DR, Han S, Kim YJ, Choi E, Bae D, Oh DH, Lee YH, Kim S, Jun W (2016). "Antistress Effects of Rosa rugosa Thunb. on Total Sleep Deprivation-Induced Anxiety-Like Behavior and Cognitive Dysfunction in Rat: Possible Mechanism of Action of 5-HT6 Receptor Antagonist". J Med Food. 19: 870–81. doi:10.1089/jmf.2016.3660. PMID 27331439.
  41. ↑ Kan R, Wang B, Zhang C, Yang Z, Ji S, Lu Z, Zheng C, Jin F, Wang L (Nov 2004). "Association of the HTR6 polymorphism C267T with late-onset Alzheimer's disease in Chinese". Neuroscience Letters. 372 (1–2): 27–9. doi:10.1016/j.neulet.2004.09.007. PMID 15531082.
  42. ↑ 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 (Mar 2002). "Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease". Neurology. 58 (5): 828–9. doi:10.1212/wnl.58.5.828. PMID 11889255.

Further reading

  • 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. 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.

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