630
Views
4
CrossRef citations to date
0
Altmetric
Reviews

The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

ORCID Icon, , , &
Pages 523-533 | Received 26 Feb 2018, Accepted 29 May 2018, Published online: 18 Jun 2018

References

  • Alzheimer’s Association. Alzheimer’s Disease Facts and Figures 2017 [cited 2017 Nov 17]. Available from: http://alz.org/documents_custom/2017-facts-and-figures.pdf. Accessed 2018 Feb 6
  • Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013 Apr;12(4):357–367. PubMed PMID: 23477989.
  • Perl DP. Neuropathology of Alzheimer’s disease. Mt Sinai J Med. 2010Jan-Feb;77(1):32–42. PubMed PMID: PMC2918894.
  • Khoury R, Patel K, Gold J, et al. Recent progress in the pharmacotherapy of Alzheimer’s disease. Drugs Aging. 2017. Nov 07. PubMed PMID: 29116600. doi: 10.1007/s40266-017-0499-x.
  • Cummings J, Lee G, Mortsdorf T, et al. Alzheimer’s disease drug development pipeline: 2017. Alzheimer’s Dementia: Translational Research Clinical Interventions. 2017 05 24;3(3):367–384. PubMed PMID: PMC5651419.
  • Xiong C, van Belle G, Miller JP, et al. Designing clinical trials to test disease-modifying agents: application to the treatment trials of Alzheimer’s disease. Clin Trials. 2011;8(1):15–26. PubMed PMID: PMC3146242.
  • Iwata A, Iwatsubo T. Disease-modifying therapy for Alzheimer’s disease: challenges and hopes. Neurol Clin Neurosci. 2013;1(2):49–54.
  • Birks J. Cholinesterase inhibitors for Alzheimer’s disease. The Cochrane Database of Systematic Reviews. 2006 Jan 25 (1):Cd005593. PubMed PMID: 16437532.
  • Winblad B, Jones RW, Wirth Y, et al. Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord. 2007;24(1):20–27.
  • Howard R, McShane R, Lindesay J, et al. Nursing home placement in the donepezil and memantine in moderate to severe Alzheimer’s disease (DOMINO-AD) trial: secondary and post-hoc analyses. Lancet Neurol. 2015 Dec;14(12):1171–1181. PubMed PMID: 26515660.
  • Patel L, Grossberg GT. Combination therapy for Alzheimer’s disease. Drugs Aging. 2011Jul 01;28(7):539–546. PubMed PMID: 21721598.
  • Rockwood K. Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer’s disease. PubMed PMID: PMC1763555 J Neurol Neurosurg Psychiatry. 2004;75(5):677–685.
  • Ali TB, Schleret TR, Reilly BM, et al. Adverse effects of cholinesterase inhibitors in dementia, according to the pharmacovigilance databases of the United-States and Canada. PloS One. 2015;10(12):e0144337. PubMed PMID: 26642212; PubMed Central PMCID: PMCPMC4671709.
  • Matsunaga S, Kishi T, Iwata N. Combination therapy with cholinesterase inhibitors and memantine for Alzheimer’s disease: a systematic review and meta-analysis. PubMed PMID: PMC4376554 Int J Neuropsychopharmacol. 2015;18(5):pyu115.
  • Lanctôt KL, Herrmann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ: Can Med Assoc J. 2003;169(6):557–564. PubMed PMID: PMC191283.
  • Ruat M, Traiffort E, Arrang JM, et al. A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochem Biophys Res Commun. 1993;193(1):268–276. PubMed PMID: 8389146 May 28.
  • Hoyer D, Martin G. 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology. 1997 Apr-May;36(4–5):419–428. PubMed PMID: 9225265.
  • Bourson A, Borroni E, Austin RH, et al. Determination of the role of the 5-ht6 receptor in the rat brain: a study using antisense oligonucleotides. J Pharmacol Exp Ther. 1995;274(1):173–180. PubMed PMID: 7616396 Jul.
  • Marcos B, Gil-Bea FJ, Hirst WD, et al. 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 Sep;24(5):1299–1306. PubMed PMID: 16987217.
  • de Jong IEM, Mork A. Antagonism of the 5-HT6 receptor - preclinical rationale for the treatment of Alzheimer’s disease. Neuropharmacology. 2017;125:50–63. PubMed PMID: 28711518 Oct
  • Schechter LE, Lin Q, Smith DL, et al. Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 [original article]. Neuropsychopharmacology. 2008;33:1323–1335.
  • Dawson LA, Nguyen HQ, Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology. 2001Nov;25(5):662–668. PubMed PMID: 11682249.
  • West PJ, Marcy VR, Marino MJ, et al. Activation of the 5-HT(6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus. Neuroscience. 2009 Dec 1;164(2):692–701. PubMed PMID: 19660530.
  • Nikiforuk A. The procognitive effects of 5-HT6 receptor ligands in animal models of schizophrenia. PubMed PMID: 24501158 Rev Neurosci. 2014;25(3):367–382.
  • Ramírez MJ. 5-HT(6)receptors and Alzheimer’s disease. Alzheimer’s Res Ther. 20130422;5(2):15. PubMed PMID: PMC3706851.
  • Fone KC. An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function. Neuropharmacology. 2008Nov;55(6):1015–1022. PubMed PMID: 18655798.
  • Dawson LA. The central role of 5-HT6 receptors in modulating brain neurochemistry. Int Rev Neurobiol. 2011;96:1–26. PubMed PMID: 21329782.
  • Upton N, Chuang TT, Hunter AJ, et al. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics: Journal Am Soc Exp NeuroTherapeutics. 2008 Jul;5(3):458–469. PubMed PMID: 18625457; PubMed Central PMCID: PMCPMC5084247.
  • Arnt J, Bang-Andersen B, Grayson B, et al. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. The International Journal of Neuropsychopharmacology. 2010 Sep;13(8):1021–1033. PubMed PMID: 20569520.
  • Herrik KF, Mørk A, Richard N, et al. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus. Neuropharmacology. 2016;107:351–363.
  • Amat-Foraster M, Leiser SC, Herrik KF, et al. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture. Neuropharmacology. 2017 Feb;113(Pt A):45–59. PubMed PMID: 27647493.
  • Ferris CF, Kulkarni P, Yee JR, et al. The serotonin receptor 6 antagonist idalopirdine and acetylcholinesterase inhibitor donepezil have synergistic effects on brain activity-a functional mri study in the awake rat. Front Pharmacol. 2017;8:279. PubMed PMID: 28659792; PubMed Central PMCID: PMCPMC5467007.
  • Wilkinson D, Windfeld K, Colding-Jorgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014 Nov;13(11):1092–1099. PubMed PMID: 25297016
  • Atri A, Frolich L, Ballard C, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. Jama. 2018 Jan 9;319(2):130–142. PubMed PMID: 29318278
  • Bennett DA. Lack of benefit with idalopirdine for Alzheimer disease: another therapeutic failure in a complex disease process. Jama. 2018Jan 9;319(2):123–125. PubMed PMID: 29318261.
  • Schmidt E, Kuwabara H, Areberg J, et al. A clinical positron emission tomography (pet) study investigating occupancy at the 5-ht6 receptor after multiple oral doses of lu ae58054 to healthy men. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association. 2014;10(4):P925.
  • Lorke DE, Lu G, Cho E, et al. Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC Neurosci. PubMed PMID: 16640790; PubMed Central PMCID: PMCPMC1523198. 2006;7:36. Apr 27.
  • de Bruin NM, van Drimmelen M, Kops M, et al. Effects of risperidone, clozapine and the 5-HT6 antagonist GSK-742457 on PCP-induced deficits in reversal learning in the two-lever operant task in male Sprague Dawley rats. Behav Brain Res. PubMed PMID: 23384714. 2013;244:15–28. May 1.
  • Idris N, Neill J, Grayson B, et al. Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT6 and 5-HT2A receptor mechanisms [journal article]. Psychopharmacology. 2009 Oct;208(1):23.
  • Callaghan CK, Hok V, Della-Chiesa A, et al. Age-related declines in delayed non-match-to-sample performance (DNMS) are reversed by the novel 5HT6 receptor antagonist SB742457. Neuropharmacology. 2012 Oct;63(5):890–897. PubMed PMID: 22766392.
  • Maher-Edwards G, Zvartau-Hind M, Hunter AJ, et al. Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s disease. Curr Alzheimer Res. 2010Aug;7(5):374–385. PubMed PMID: 20043816
  • Maher-Edwards G, Dixon R, Hunter J, et al. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011 May;26(5):536–544. PubMed PMID: 20872778.
  • Maher-Edwards G, Watson C, Ascher J, et al. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer’s disease. Alzheimer’s Dementia: Translational Research Clinical Interventions. 2015;1(1):23–36.
  • Study Evaluating Intepirdine (RVT-101) in subjects with mild to moderate Alzheimer’s disease on donepezil: MINDSET study 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT02585934. Accessed on 2018 Feb 20
  • Axovant Announces Negative Topline Results of Intepirdine Phase 3 MINDSET Trial in Alzheimer’s Disease 2017. Available from: https://www.prnewswire.com/news-releases/axovant-announces-negative-topline-results-of-intepirdine-phase-3-mindset-trial-in-alzheimers-disease-300525711.html. Accessed on 2018 Feb 20.
  • Axovant Announces Negative Results for Intepirdine in Phase 2b HEADWAY and Pilot Phase 2 Gait and Balance Studies; Positive Trends in Efficacy Seen in Pilot Phase 2 Nelotanserin Study 2018 [ updated 1/8/2018;2/13/2018]. Available from: https://globenewswire.com/news-release/2018/01/08/1284918/0/en/Axovant-Announces-Negative-Results-for-Intepirdine-in-Phase-2b-HEADWAY-and-Pilot-Phase-2-Gait-and-Balance-Studies-Positive-Trends-in-Efficacy-Seen-in-Pilot-Phase-2-Nelotanserin-Stu.html#.Wmf0a7XfXuE.email. Accessed on 2018 Feb 13].
  • Nirogi R, Shinde A, Kambhampati RS, et al. Discovery and development of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indol e dimesylate monohydrate (SUVN-502): a novel, potent, selective and orally active serotonin 6 (5-HT6) receptor antagonist for potential treatment of Alzheimer’s disease. J Med Chem. 2017 Mar 9;60(5):1843–1859. PubMed PMID: 28212021
  • Nirogi R, Mudigonda K, Penta KK, et al. Safety, tolerability, and pharmacokinetics of a potent and selective 5-ht6 receptor antagonist, SUVN-502, following multiple ascending doses in healthy elderly subjects, and effect of gender and food on single-dose pharmacokinetics. Alzheimer’s & Dementia. 2015;11(7):P748.
  • SUVN-502 With donepezil and memantine for the treatment of moderate Alzheimer’s disease- phase 2a study [updated February 1, 2018]. Available from: https://clinicaltrials.gov/ct2/show/NCT02580305?term=NCT02580305&rank=1. Accessed on 2018 Feb 20 .
  • Xu Y, Yan J, Zhou P, et al. Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol. 2012 02 25;97(1):1–13. PubMed PMID: PMC3371373.
  • Ivachtchenko AV, Okun I, Aladinskiy V, et al. AVN-492, A novel highly selective 5-HT6R antagonist: preclinical evaluation. Journal of Alzheimer’s Disease: JAD. 2017;58(4):1043–1063. PubMed PMID: 28550249.
  • Schneider LS. Idalopirdine for Alzheimer’s disease: written in the stars. Lancet Neurol. 2014Nov;13(11):1063–1065. PubMed PMID: 25297011.
  • Calhoun A, Ko J, Grossberg GT. Emerging chemical therapies targeting 5-hydroxytryptamine in the treatment of Alzheimer’s disease. Expert Opin Emerg Drugs. 2017Mar;22(1):101–105. PubMed PMID: 28253832.
  • Fullerton T, Binneman B, David W, et al. A phase 2 clinical trial of pf-05212377 (sam-760) in subjects with mild to moderate alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association. 2016;12(7):P419.
  • Bezprozvanny I. The rise and fall of Dimebon. PubMed PMID: PMC3922928 Drug News Perspect. 2010;23(8):518–523.
  • Ferrero H, Solas M, Francis PT, et al. Serotonin 5-HT6 receptor antagonists in Alzheimer’s disease: therapeutic rationale and current development status. CNS Drugs. 2017;31(1):19–32. 10.1007/s40263–016–0399–3. PubMed PMID: 27914038 Jan.
  • Karila D, Freret T, Bouet V, et al. Therapeutic potential of 5-HT6 receptor agonists. J Med Chem. 2015;58(20):7901–7912.
  • Vanda D, Soural M, Canale V, et al. Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties. Eur J Med Chem. PubMed PMID: 29291439. 2018;144:716–729. Jan 20.
  • Sgambato-Faure V, Billard T, Météreau E, et al. Characterization and reliability of [18F]2FNQ1P in cynomolgus monkeys as a PET radiotracer for serotonin 5-HT6 receptors. Front Pharmacol. 2017;8:471. PubMed PMID: PMC5513908.
  • de Bruin NMWJ, Kruse CG. 5-HT6 receptor antagonists: potential efficacy for the treatment of cognitive impairment in schizophrenia. Curr Pharm Des. 2015;21(26): 3739–3759. PubMed PMID: 26044973.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.