The serotonin 5-HT6 receptor: A viable drug target for treating cognitive deficits in Alzheimer's disease

Expert Review of Neurotherapeutics

Volumn 9, Issue 7, 2009, Pages 1073-1085

  Geldenhuys, Werner J ^a   Van Der Schyf, Cornelis J ^a  

^a NORTHEAST OHIO MEDICAL UNIVERSITY   (United States)

Author keywords

5 HT6 antagonist; Amyloid ; Cholinesterase inhibitor; Dementia; Donepezil; Memantine; Nootropic

Indexed keywords

1 BENZENESULFONYL 5 METHOXY N,N DIMETHYLTRYPTAMINE; 2 ETHYL 5 METHOXY N,N DIMETHYLTRYPTAMINE; 2 PHENYL 5 METHOXY N,N DIMETHYLTRYPTAMINE; 4 AMINO N [2,6 BIS(METHYLAMINO) 4 PYRIMIDINYL]BENZENESULFONAMIDE; 5 CHLORO N [4 METHOXY 3 (1 PIPERAZINYL)PHENYL] 3 METHYL 2 BENZOTHIOPHENESULFONAMIDE; ANTISENSE OLIGONUCLEOTIDE; ATYPICAL ANTIPSYCHOTIC AGENT; BVT 74316; CHOLINESTERASE INHIBITOR; CLOZAPINE; DIZOCILPINE; DONEPEZIL; GALANTAMINE; HALOPERIDOL; LY 483518; MEMANTINE; OLANZAPINE; PIPERAZINE DERIVATIVE; PRX 07034; RISPERIDONE; RIVASTIGMINE; SB 399885; SB 742457; SEROTONIN 6 ANTAGONIST; SEROTONIN 6 RECEPTOR; SGS 518; SYN 114; TRICYCLIC ANTIDEPRESSANT AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG; WAY 181187; SEROTONIN ANTAGONIST; SEROTONIN RECEPTOR;

ALZHEIMER DISEASE; ANXIETY DISORDER; COGNITION; COGNITIVE DEFECT; DRUG ANTAGONISM; DRUG PENETRATION; DRUG POTENCY; DRUG POTENTIATION; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG TARGETING; HUMAN; MEMORY; MEMORY DISORDER; NONHUMAN; OBESITY; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION; ANIMAL; BIOLOGICAL MODEL; CHEMISTRY; DRUG DESIGN; METABOLISM;

ALZHEIMER DISEASE; ANIMALS; COGNITION DISORDERS; DRUG DESIGN; HUMANS; MODELS, BIOLOGICAL; RECEPTORS, SEROTONIN; SEROTONIN ANTAGONISTS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 67651049001     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.09.51     Document Type: Review

References (80)

1. Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ 178(5), 548-556 (2008).
2. Chertkow H, Massoud F, Nasreddine Z et al. Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia. CMAJ 178(10), 1273-1285 (2008). (Pubitemid 351678349)
3. Hogan DB, Bailey P, Black S et al. Diagnosis and treatment of dementia: 4. Approach to management of mild to moderate dementia. CMAJ 179(8), 787-793 (2008).
4. Hebert LE, Scherr PA, Beckett LA et al. Age-specific incidence of Alzheimer's disease in a community population. JAMA 273(17), 1354-1359 (1995). • Describes the incidence of Alzheimer's disease (AD) in populations and possible future trends.
5. Narahashi T, Moriguchi S, Zhao X, Marszalec W, Yeh JZ. Mechanisms of action of cognitive enhancers on neuroreceptors. Biol. Pharm. Bull. 27(11), 1701-1706 (2004). (Pubitemid 41701591)
6. Toda N, Tago K, Marumoto S et al. Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. Bioorg. Med. Chem. 11(9), 1935-1955 (2003).
7. Snape MF, Misra A, Murray TK et al. A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066. Neuropharmacology 38(1), 181-193 (1999). (Pubitemid 29073537)
8. Abe Y, Aoyagi A, Hara T et al. Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease. J. Pharmacol. Sci. 93(1), 95-105 (2003). (Pubitemid 37254273)
9. 6) receptor and pharmacology of the GABA, glutamate and cholinergic systems.
10. Courtney C, Farrell D, Gray R et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 363(9427), 2105-2115 (2004).
11. 6 receptors in learning and memory. Trends Pharmacol. Sci. 29(9), 482-492 (2008).
12. Farlow MR, Miller ML, Pejovic V. Treatment options in Alzheimer's disease: maximizing benefit, managing expectations. Dement. Geriatr. Cogn. Disord. 25(5), 408-422 (2008). (Pubitemid 351630074)
13. Bojarski L, Herms J, Kuznicki J. Calcium dysregulation in Alzheimer's disease. Neurochem. Int. 52(4-5), 621-633 (2008).
14. Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse. Neuropharmacology 53(6), 699-723 (2007). (Pubitemid 47532143)
15. Emre M, Mecocci P, Stender K. Pooled analyses on cognitive effects of memantine in patients with moderate to severe Alzheimer's disease. J. Alzheimers Dis. 14(2), 193-199 (2008). (Pubitemid 352040033)
16. Danysz W, Parsons CG. The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence. Int. J. Geriatr. Psychiatry 18(Suppl. 1), S23-S32 (2003). (Pubitemid 37150475)
17. Molinuevo JL, Llado A, Rami L. Memantine: targeting glutamate excitotoxicity in Alzheimer's disease and other dementias. Am. J. Alzheimers Dis. Other Demen. 20(2), 77-85 (2005). (Pubitemid 40547347)
18. Sadowski M, Wisniewski T. Disease modifying approaches for Alzheimer's pathology. Curr. Pharm. Des. 13(19), 1943-1954 (2007).
19. Wisniewski T, Sadowski M. Preventing β-amyloid fibrillization and deposition: β-sheet breakers and pathological chaperone inhibitors. BMC Neurosci. 9(Suppl. 2), S5 (2008).
20. Wolfe MS. Selective amyloid-βlowering agents. BMC Neurosci. 9(Suppl. 2), S4 (2008).
21. Marksteiner J, Schmidt R. Tre atment strategies in Alzheimer's disease with a focus on early pharmacological interventions. Drugs Aging 21(7), 415-426 (2004). (Pubitemid 38736887)
22. 6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. Br. J. Pharmacol. 155(3), 434-440 (2008).
23. Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE. Serotonergic drugs : effects on appetite expression and use for the treatment of obesity. Drugs 67(1), 27-55 (2007).
24. 6 receptors: a novel target for cognitive enhancement. Pharmacol. Ther. 108(3), 320-333 (2005).
25. 6 receptor.
26. Monsma FJ Jr, 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. 43(3), 320-327 (1993). •• First report on cloning of the 5-HT6 receptor. (Pubitemid 23081986)
27. 6 receptor.
28. 7 receptors. In: Annual Reports in Medicinal Chemistry. Macor JE (Ed.). Academic Press, CA, USA 25-42 (2008).
29. 6 receptor antagonists in obesity.
30. 6 receptor antagonist.
31. Otano A, Frechilla D, Cobreros A et al. Anxiogenic-like effects and reduced stereological counting of immunolabelled 5-hydroxytryptamine 6 receptors in rat nucleus accumbens by antisense oligonucleotides. Neuroscience 92(3), 1001-1009 (1999). (Pubitemid 29287545)
32. Hirst WD, Abrahamsen B, Blaney FE et al. Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol. Pharmacol. 64(6), 1295-1308 (2003). (Pubitemid 37532219)
33. 6 receptor polymorphism C267T in Alzheimer's disease. Neurosci. Lett. 276(2), 138-139 (1999).
34. 6 receptor polymorphism C267T with depression in patients with Alzheimer's disease. Psych. Clin. Neurosci. 55(4), 427-429 (2001).
35. Pakaski M, Kalman J. Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease. Neurochem. Int. 53(5), 103-111 (2008).
36. Christensen DZ, Kraus SL, Flohr A, Cotel MC, Wirths O, Bayer TA. Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice. Acta Neuropathol. 116(6), 647-655 (2008).
37. Christensen DZ, Bayer TA, Wirths O. Intracellular Aβ triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol. Aging (2008) (Epub ahead of print).
38. 6 receptors in cognitive and non-cognitive symptoms in Alzheimer's disease. Neuropsychopharmacology 29(2), 410-416 (2004).
39. Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M et al. Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease. Neuropsychologia 43(3), 442-449 (2005). (Pubitemid 40222131)
40. Gil-Bea FJ, Garcia-Alloza M, Dominguez J, Marcos B, Ramirez MJ. Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit. Neurosci. Lett. 375(1), 37-41 (2005). (Pubitemid 40139064)
41. 6 receptor function in behavioral symptoms of Alzheimer's disease. J. Alzheimers Dis. 14(1), 43-50 (2008).
42. 6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology (Berl.) 158(2), 114-119 (2001).
43. Jellinger KA. Alzheimer 100 - highlights in the history of Alzheimer research. J. Neural. Transm. 113(11), 1603-1623 (2006).
44. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neurol. 2(9), 539-547 (2003). (Pubitemid 36994993)
45. 6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur. J. Pharmacol. 553(1-3), 109-119 (2006).
46. 6 receptor antagonist, Ro 04-6790. Psychopharmacology (Berl.) 170(4), 358-367 (2003).
47. 6 receptor antagonist, Ro 04-6790, in rats. Br. J. Pharmacol. 126(7), 1537-1542 (1999).
48. 6 receptor: localization and function. Ann. NY Acad. Sci. 861, 91-96 (1998).
49. 6 receptors in nigro-striatal function in rodents. Br. J. Pharmacol. 125(7), 1562-1566 (1998).
50. Shirazi-Southall S, Rodriguez DE, Nomikos GG. Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat. Neuropsychopharmacology 26(5), 583-594 (2002). (Pubitemid 34260977)
51. 6 receptor antagonist. J. Med. Chem. 46(7), 1273-1276 (2003).
52. 6 receptor-like material in the rat central nervous system. Brain Res. 746(1-2), 207-219 (1997).
53. 6 receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology 29(1), 93-100 (2004).
54. 6 receptor-mediated acetylcholine release. Eur. J. Neurosci. 24(5), 1299-1306 (2006). • Evidence suggesting that neuronal pathways other than cholinergic neurons are involved in cognition.
55. 6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytryptamine-treated rats. Synapse 23(3), 164-173 (1996).
56. 6) receptor antagonists in rodent models of learning. J. Pharmacol. Exp. Ther. 307(2), 682-691 (2003).
57. 6 receptor antagonist SB-399885: the impact of benzodiazepine receptors. Eur. J. Pharmacol. 580(3), 355-360 (2008).
58. 6 receptor ligands and their biological functions. Curr. Top. Med. Chem. 2(6), 643-654 (2002).
59. 6 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 (2004).
60. Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat. Neurosci. 5(Suppl.), 1039-1042 (2002).
61. 6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology 33(6), 1323-1335 (2008).
62. 6 receptor agonist. J. Med. Chem. 50(23), 5535-5538 (2007).
63. 6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats. Neuropharmacology 54(8), 1166-1174 (2008).
64. 6 receptor antagonists may be useful in schizophrenia.
65. Moghaddam B, Roth RH, Bunney BS. Characterization of dopamine release in the rat medial prefrontal cortex as assessed by in vivo microdialysis: comparison to the striatum. Neuroscience 36(3), 669-676 (1990). (Pubitemid 20282181)
66. 7. J. Med. Chem. 46(14), 2795-2812 (2003). •• Excellent review on the medicinal chemistry of newer serotonin receptor antagonists.
67. 6 receptors. Bioorg. Med. Chem. Lett. 16(22), 5832-5835 (2006).
68. 6 antagonists. Bioorg. Med. Chem. 12(15), 3977-3985 (2004).
69. 6 receptors. Bioorg. Med. Chem. Lett. 14(17), 4569-4573 (2004).
70. 6) receptor antagonists. J. Med. Chem. 48(13), 4216-4219 (2005).
71. 6 ligands from common feature pharmacophore hypotheses. J. Chem. Inf. Model. 48(1), 197-206 (2008).
72. 6 serotonin receptors: receptor modeling studies. J. Med. Chem. 51(3), 603-611 (2008).
73. 6 serotonin antagonist MS-245 on the actions of (-)nicotine. Pharmacol. Biochem. Behav. 85(1), 170-177 (2006).
74. 6 receptors. Bioorg. Med. Chem. Lett. 15(15), 3510-3513 (2005).
75. 6 serotonin receptor ligands. Bioorg. Med. Chem. Lett. 15(6), 1707-1711 (2005).
76. 6 antagonist MS-245. Pharmacol. Biochem. Behav. 78(2), 263-268 (2004).
77. 6 serotonin receptor ligands. Bioorg. Med. Chem. Lett. 14(8), 1961-1964 (2004).
78. 6 antagonists. Bioorg. Med. Chem. Lett. 10(20), 2295-2299 (2000).
79. 6 receptor antagonists for the treatment of Alzheimer's disease. Curr. Top. Med. Chem. 8(12), 1035-1048 (2008).
80. 6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Discov. Today 11(7-8), 283-299 (2006).