Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 2/2013

01-04-2013 | Review

5-HT6 receptors and Alzheimer's disease

Author: María Javier Ramírez

Published in: Alzheimer's Research & Therapy | Issue 2/2013

Login to get access

Abstract

During the past 20 years, the 5-HT6 receptor has received increasing attention and become a promising target for improving cognition. Several studies with structurally different compounds have shown that not only antagonists but also 5-HT6 receptor agonists improve learning and memory in animal models. A large number of publications describing the development of ligands for this receptor have come to light, and it is now quite evident that 5-HT6 receptors have great pharmaceutical potential in terms of related patents. However, 5-HT6 receptor functionality is much more complex than initially defined. According to the existing data, different cellular pathways may be activated, depending on the drug being used. This article reviews preclinical and clinical evidence of the effects that 5-HT6 receptor compounds have on cognition. In addition, the biochemical and neurochemical mechanisms of action through which 5-HT6 receptor compounds can influence cognition will be described. Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease.
Appendix
Available only for authorised users
Literature
1.
Francis PT, Ramírez MJ, Lai MK: Neurochemical basis for symptomatic treatment of Alzheimer's disease. Neuropharmacol. 2010, 59: 221-229. 10.1016/j.neuropharm.2010.02.010.CrossRef
2.
Codony X, Vela JM, Ramírez MJ: 5-HT(6) receptor and cognition. Curr Opin Pharmacol. 2011, 11: 94-100. 10.1016/j.coph.2011.01.004.CrossRefPubMed
3.
Marazziti D, Baroni S, Catena Dell'Osso M, Bordi F, Borsini F: Serotonin receptors of type 6 (5-HT6): what can we expect from them?. Curr Med Chem. 2011, 18: 2783-2790. 10.2174/092986711796011283.CrossRefPubMed
4.
Meneses A, Pérez-García G, Ponce-Lopez T, Castillo C: 5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes. Int Rev Neurobiol. 2011, 96: 27-24.CrossRefPubMed
5.
Monsma FJ, Shen Y, Ward RP, Hamblin MW, Sibley DR: Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 1993, 43: 320-327.PubMed
6.
Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW: Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. J Neurochem. 1996, 66: 47-56.CrossRefPubMed
7.
Ruat M, Traiffort E, Arrang JM, Tardivel-Lacombe J, Diaz J, Leurs R, Schwartz JC: A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochem Biophys Res Commun. 1993, 193: 268-276. 10.1006/bbrc.1993.1619.CrossRefPubMed
8.
Gérard C, Martres MP, Lefevre K, Miquel MC, Verge D, Lanfumey L, Doucet E, Hamon M, El Mestikawy S: Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain Res. 1997, 746: 207-219. 10.1016/S0006-8993(96)01224-3.CrossRefPubMed
9.
Hamon M, Doucet E, Lefevre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Verge D: Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors. Neuropsychopharmacol. 1999, 21: 68S-76S.
10.
de Foubert G, O'Neill MJ, Zetterström TS: Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression. Neuroscience. 2007, 147: 778-785. 10.1016/j.neuroscience.2007.04.045.CrossRefPubMed
11.
Fone KC: An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function. Neuropharmacology. 2008, 55: 1015-1022. 10.1016/j.neuropharm.2008.06.061.CrossRefPubMed
12.
Dupuis DS, Mannoury la Cour C, Chaput C, Verrièle L, Lavielle G, Millan MJ: Actions of novel agonists, antagonists and antipsychotic agents at recombinant rat 5-HT6 receptors: a comparative study of coupling to G alphas. Eur J Pharmacol. 2008, 588: 170-177. 10.1016/j.ejphar.2008.04.039.CrossRefPubMed
13.
Zhang JY, Nawoschik S, Kowal D, Smith D, Spangler T, Ochalski R, Schechter L, Dunlop J: Characterization of the 5-HT6 receptor coupled to Ca2+ signalling using an enabling chimeric G-protein. Eur J Pharmacol. 2003, 472: 33-38. 10.1016/S0014-2999(03)01855-7.CrossRefPubMed
14.
Yun HM, Kim S, Kim H, Kostenis E, Kim JI, Seong JY, Baik JH, Rhim H: The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. J Biol Chem. 2007, 282: 5496-5505.CrossRefPubMed
15.
Marcos B, Cabero M, Solas M, Aisa B, Ramirez MJ: Signalling pathways associated with 5-HT6 receptors: relevance for cognitive effects. Int J Neuropsychopharmacol. 2010, 13: 775-784. 10.1017/S146114570999054X.CrossRefPubMed
16.
Yun HM, Baik JH, Kang I, Jin C, Rhim H: Physical interaction of Jab1 with human serotonin 6 G-protein-coupled receptor and their possible roles in cell survival. J Biol Chem. 2010, 285: 10016-10029. 10.1074/jbc.M109.068759.PubMedCentralCrossRefPubMed
17.
Yun HM, Rhim H: 5-HT6 receptor ligands, EMD386088 and SB258585, differentially regulate 5-HT6 receptor-independent events. Toxicol In Vitro. 2011, 25: 2035-2040. 10.1016/j.tiv.2011.08.004.CrossRefPubMed
18.
Gérard C, el Mestikawy S, Lebrand C, Adrien J, Ruat M, Traiffort E, Hamon M, Martres MP: Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytryptamine-treated rats. Synapse. 1996, 23: 164-173. 10.1002/(SICI)1098-2396(199607)23:3<164::AID-SYN5>3.0.CO;2-6.CrossRefPubMed
19.
Marcos B, Gil-Bea FJ, Hirst WD, García-Alloza M, Ramírez MJ: Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release. Eur J Neurosci. 2006, 24: 1299-1306. 10.1111/j.1460-9568.2006.05003.x.CrossRefPubMed
20.
Riemer C, Borroni E, Levet-Trafit B, Martin JR, Poli S, Porter RH, Bös M: Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. J Med Chem. 2003, 46: 1273-1276. 10.1021/jm021085c.CrossRefPubMed
21.
Dawson LA, Nguyen HQ, Li P: The 5-HT6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology. 2001, 25: 662-668. 10.1016/S0893-133X(01)00265-2.CrossRefPubMed
22.
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: Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology. 2008, 33: 1323-1335. 10.1038/sj.npp.1301503.CrossRefPubMed
23.
Tassone A, Madeo G, Schirinzi T, Vita D, Puglisi F, Ponterio G, Borsini F, Pisani A, Bonsi P: Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission. Neuropharmacology. 2011, 61: 632-637. 10.1016/j.neuropharm.2011.05.004.CrossRefPubMed
24.
Woolley ML, Marsden CA, Fone KC: 5-ht6 receptors. Curr Drug Targets. 2004, 3: 59-79.
25.
West PJ, Marcy VR, Marino MJ, Schaffhauser H: Activation of the 5-HT(6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus. Neuroscience. 2009, 164: 692-701. 10.1016/j.neuroscience.2009.07.061.CrossRefPubMed
26.
Ivachtchenko AV, Ivanenkov YA, Tkachenko SE: 5-hydroxytryptamine subtype 6 receptor modulators: a patent survey. Expert Opin Ther. 2010, 20: 1171-1196. 10.1517/13543776.2010.494661.CrossRef
27.
28.
Riccioni T, Bordi F, Minetti P, Spadoni G, Yun HM, Im BH, Tarzia G, Rhim H, Borsini F: ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors. Eur J Pharmacol. 2011, 661: 8-14. 10.1016/j.ejphar.2011.04.028.CrossRefPubMed
29.
Henderson AJ, Guzzo PR, Ghosh A, Kaur J, Koo JM, Nacro K, Panduga S, Pathak R, Shimpukade B, Tan V, Xiang K, Wierschke JD, Isherwood ML: Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists. Bioorg Med Chem Lett. 2012, 22: 1494-1498. 10.1016/j.bmcl.2012.01.022.CrossRefPubMed
30.
Nirogi RV, Kambhampati R, Kothmirkar P, Konda J, Bandyala TR, Gudla P, Arepalli S, Gangadasari NP, Shinde AK, Deshpande AD, Dwarampudi A, Chindhe AK, Dubey PK: Synthesis and structure-activity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands. J Enzyme Inhib Med Chem. 2012, 27: 443-450. 10.3109/14756366.2011.595713.CrossRefPubMed
31.
Nirogi RV, Kambhampati R, Daulatabad AV, Gudla P, Shaikh M, Achanta PK, Shinde AK, Dubey PK: Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands. J Enzyme Inhib Med Chem. 2011, 26: 341-349. 10.3109/14756366.2010.510471.CrossRef
32.
Hajjo R, Setola V, Roth BL, Tropsha A: Chemocentric informatics approach to drug discovery: identification and experimental validation of selective estrogen receptor modulators as ligands of 5-hydroxytryptamine-6 receptors and as potential cognition enhancers. J Med Chem. 2012, 55: 5704-5719. 10.1021/jm2011657.PubMedCentralCrossRefPubMed
33.
Liu F, Majo VJ, Prabhakaran J, Milak MS, John Mann J, Parsey RV, Kumar JS: Synthesis and in vivo evaluation of [O-methyl-11C] N-[3,5-dichloro-2(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide as an imaging probe for 5-HT6 receptors. Bioorg Med Chem. 2011, 19: 5255-5259. 10.1016/j.bmc.2011.06.090.CrossRefPubMed
34.
Parker CA, Gunn RN, Rabiner EA, Slifstein M, Comley R, Salinas C, Johnson CN, Jakobsen S, Houle S, Laruelle M, Cunningham VJ, Martarello L: Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor. J Nucl Med. 2012, 53: 295-303. 10.2967/jnumed.111.093419.CrossRefPubMed
35.
Meneses A: Effects of the 5-HT6 receptor antagonist Ro 04-6790 on learning consolidation. Behav Brain Res. 2001, 118: 107-110. 10.1016/S0166-4328(00)00316-8.CrossRefPubMed
36.
Huerta-Rivas A, Pérez-García G, González-Espinosa C, Meneses A: Time-course of 5-HT6(6) receptor mRNA expression during memory consolidation and amnesia. Neurobiol Learn Mem. 2010, 93: 99-110. 10.1016/j.nlm.2009.08.009.CrossRefPubMed
37.
Mitchell ES, Sexton T, Neumaier JF: Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning. Neuropsychopharmacology. 2007, 32: 1520-1530. 10.1038/sj.npp.1301284.CrossRefPubMed
38.
Hirst WD, Stean TO, Rogers DC, Sunter D, Pugh P, Moss SF, Bromidge SM, Riley G, Smith DR, Bartlett S, Heidbreder CA, Atkins AR, Lacroix LP, Dawson LA, Foley AG, Regan CM, Upton N: SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur J Pharmacol. 2006, 553: 109-119. 10.1016/j.ejphar.2006.09.049.CrossRefPubMed
39.
Da Silva Costa-Aze V, Dauphin F, Boulouard M: 5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice. Psychopharmacology. 2012, 2221: 99-115.CrossRef
40.
de Bruin NM, Prickaerts J, van Loevezijn A, Venhorst J, de Groote L, Houba P, Reneerkens O, Akkerman S, Kruse CG: Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiol Learn Mem. 2011, 96: 392-402. 10.1016/j.nlm.2011.06.015.CrossRefPubMed
41.
Marcos B, Chuang TT, Gil-Bea FJ, Ramírez MJ: Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. Br J Pharmacol. 2008, 155: 434-440.PubMedCentralCrossRefPubMed
42.
Arnt J, Bang-Andersen B, Grayson B, Bymaster FP, Cohen MP, DeLapp NW, Giethlen B, Kreilgaard M, McKinzie DL, Neill JC, Nelson DL, Nielsen SM, Poulsen MN, Schaus JM, Witten LM: Lu AE58054, a 5-HT(6) antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol. 2010, 13: 1021-1033. 10.1017/S1461145710000659.CrossRefPubMed
43.
Marcos B, Aisa B, Ramírez MJ: Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: cognitive implications. Neuropharmacology. 2010, 54: 708-714.CrossRef
44.
Russell MG, Dias R: Memories are made of this (perhaps): a review of serotonin 5-HT(6) receptor ligands and their biological functions. Curr Top Med Chem. 2002, 2: 643-654. 10.2174/1568026023393877.CrossRefPubMed
45.
Lindner MD, Hodges DB, Hogan JB, Orie AF, Corsa JA, Barten DM, Polson C, Robertson BJ, Guss VL, Gillman KW, Rose GM, Jones KM, Gribkoff VK: An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning. J Pharmacol Exp Ther. 2003, 307: 682-691. 10.1124/jpet.103.056002.CrossRefPubMed
46.
Gravius A, Laszy J, Pietraszek M, Sághy K, Nagel J, Chambon C, Wegener N, Valastro B, Danysz W, Gyertyán I: 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. 2011, 22: 122-135. 10.1097/FBP.0b013e328343d804.CrossRefPubMed
47.
Kendall I, Slotten HA, Codony X, Burgueño J, Pauwels PJ, Vela JM, Fone KC: E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat. Psychopharmacology. 2011, 213: 413-430. 10.1007/s00213-010-1854-3.CrossRefPubMed
48.
Garcia-Alloza M, Hirst WD, Chen CP, Lasheras B, Francis PT, Ramírez MJ: Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer's disease. Neuropsychopharmacology. 2004, 29: 410-416. 10.1038/sj.npp.1300330.CrossRefPubMed
49.
Marcos B, García-Alloza M, Gil-Bea FJ, Chuang TT, Francis PT, Chen CP, Tsang SW, Lai MK, Ramirez MJ: Involvement of an altered 5-HT6-{6} receptor function in behavioral symptoms of Alzheimer's disease. J Alz Dis. 2008, 14: 43-50.
50.
Hirano K, Piers TM, Searle KL, Miller ND, Rutter AR, Chapman PF: Procognitive 5-HT6 antagonists in the rat forced swimming test: potential therapeutic utility in mood disorders associated with Alzheimer's disease. Life Sci. 2009, 84: 558-562. 10.1016/j.lfs.2009.01.019.CrossRefPubMed
51.
52.
Upton N, Chuang TT, Hunter AJ, Virley DJ: 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008, 5: 458-469. 10.1016/j.nurt.2008.05.008.CrossRefPubMed
53.
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, dimebon investigators: Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008, 372: 207-215. 10.1016/S0140-6736(08)61074-0.CrossRefPubMed
54.
Metadata
Title
5-HT6 receptors and Alzheimer's disease
Author
María Javier Ramírez
Publication date
01-04-2013
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 2/2013
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/alzrt169

Other articles of this Issue 2/2013

Alzheimer's Research & Therapy 2/2013 Go to the issue

Review

Biomarkers for Alzheimer's disease in plasma, serum and blood - conceptual and practical problems

Letter

Plasma tau levels in Alzheimer's disease

Research

Modeling the heterogeneity in risk of progression to Alzheimer's disease acrosscognitive profiles in mild cognitive impairment

Research

Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models

Review

Targeting norepinephrine in mild cognitive impairment and Alzheimer's disease

Research

Neuroprotective effects of D-Ala2GIP on Alzheimer's disease biomarkers in an APP/PS1 mouse model