Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease.

Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.

[1]  Greg A. Hostetler,et al.  In Search of Potent 5‐HT6 Receptor Inverse Agonists , 2014, Chemical biology & drug design.

[2]  Karla K Kopec,et al.  Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 receptor antagonists. , 2014, Bioorganic & medicinal chemistry letters.

[3]  Craig W Lindsley,et al.  Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease. , 2013, Drug discovery today.

[4]  R. Stevens,et al.  Structural Features for Functional Selectivity at Serotonin Receptors , 2013, Science.

[5]  D. Le Bars,et al.  Current status of positron emission tomography radiotracers for serotonin receptors in humans. , 2013, Journal of labelled compounds & radiopharmaceuticals.

[6]  A. A. Ivanenkov.  Small Molecule 5-HT6R Ligands: A Comprehensive Insight into their Selectivity and Activity , 2013 .

[7]  M. Babu,et al.  Molecular signatures of G-protein-coupled receptors , 2013, Nature.

[8]  R. Nirogi,et al.  Design, synthesis and pharmacological evaluation of 4-(piperazin-1-yl methyl)-N₁-arylsulfonyl indole derivatives as 5-HT₆ receptor ligands. , 2012, Bioorganic & medicinal chemistry letters.

[9]  R. Nirogi,et al.  Design, synthesis, and pharmacological evaluation of piperidin-4-yl amino aryl sulfonamides: novel, potent, selective, orally active, and brain penetrant 5-HT₆ receptor antagonists. , 2012, Journal of medicinal chemistry.

[10]  Alan A. Wilson,et al.  Biodistribution and Radiation Dosimetry of the Serotonin 5-HT6 Ligand [11C]GSK215083 Determined from Human Whole-Body PET , 2012, Molecular Imaging and Biology.

[11]  Y. Ivanenkov,et al.  5HT6 receptor antagonists: a patent update. Part 1. Sulfonyl derivatives , 2012, Expert opinion on therapeutic patents.

[12]  A. Verkhratsky,et al.  The serotonergic system in ageing and Alzheimer's disease , 2012, Progress in Neurobiology.

[13]  I. Okun,et al.  Antagonists of 5-HT₆ receptors. Substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines-Synthesis and 'structure-activity' relationship. , 2012, Bioorganic & medicinal chemistry letters.

[14]  Ying Xia,et al.  Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease , 2012, Progress in Neurobiology.

[15]  K. Nacro,et al.  Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists. , 2012, Bioorganic & medicinal chemistry letters.

[16]  Karla K Kopec,et al.  Discovery of 7-arylsulfonyl-1,2,3,4, 4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridines: identification of a potent and selective 5-HT₆ receptor antagonist showing activity in rat social recognition test. , 2012, Bioorganic & medicinal chemistry letters.

[17]  S. Tkachenko,et al.  Synthesis and structure-activity relationship (SAR) of (5,7-disubstituted 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamines as potent serotonin 5-HT(6) receptor (5-HT(6)R) antagonists. , 2011, Journal of medicinal chemistry.

[18]  H. Parri,et al.  Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease. , 2011, Biochemical pharmacology.

[19]  N. Herrmann,et al.  The Role of Dopamine in Symptoms and Treatment of Apathy in Alzheimer's Disease , 2011, CNS neuroscience & therapeutics.

[20]  J. Venhorst,et al.  N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT₆R) antagonists with unique structural features. , 2011, Journal of medicinal chemistry.

[21]  J. Venhorst,et al.  Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats , 2011, Neurobiology of Learning and Memory.

[22]  W. Geldenhuys,et al.  Role of Serotonin in Alzheimer’s Disease , 2011, CNS drugs.

[23]  A. Terry,et al.  Alzheimer's disease and age-related memory decline (preclinical) , 2011, Pharmacology Biochemistry and Behavior.

[24]  M. Gold,et al.  SB‐742457 and donepezil in Alzheimer disease: a randomized, placebo‐controlled study , 2011, International journal of geriatric psychiatry.

[25]  F. Bordi,et al.  5-HT6 pharmacology inconsistencies , 2011, Pharmacology Biochemistry and Behavior.

[26]  S. Tkachenko,et al.  2-Substituted 5,6-dimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines: new series of highly potent and specific serotonin 5-HT6 receptor antagonists. , 2011, European journal of medicinal chemistry.

[27]  A. Palmer,et al.  Neuroprotective therapeutics for Alzheimer's disease: progress and prospects. , 2011, Trends in pharmacological sciences.

[28]  M. Ramírez,et al.  5-HT(6) receptor and cognition. , 2011, Current opinion in pharmacology.

[29]  L. Tan,et al.  Roles of β-adrenergic receptors in Alzheimer's disease: Implications for novel therapeutics , 2011, Brain Research Bulletin.

[30]  T. Comery,et al.  5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists. , 2010, Journal of medicinal chemistry.

[31]  M. Carter,et al.  The Development of New Therapeutics for Alzheimer's Disease , 2010, Clinical pharmacology and therapeutics.

[32]  J. A. González-Vera,et al.  Development of molecular probes for the human 5-HT(6) receptor. , 2010, Journal of medicinal chemistry.

[33]  Ben Grayson,et al.  Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. , 2010, The international journal of neuropsychopharmacology.

[34]  F. LaFerla.  Pathways linking Abeta and tau pathologies. , 2010, Biochemical Society transactions.

[35]  M. Gold,et al.  Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. , 2010, Current Alzheimer research.

[36]  M. Solas,et al.  Signalling pathways associated with 5-HT6 receptors: relevance for cognitive effects. , 2010, The international journal of neuropsychopharmacology.

[37]  A. Wesołowska.  Potential role of the 5-HT_6 receptor in depression and anxiety: an overview of preclinical data , 2010, Pharmacological reports : PR.

[38]  B. Winblad,et al.  Alzheimer's disease: clinical trials and drug development , 2010, The Lancet Neurology.

[39]  S. Tkachenko,et al.  (3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: potent and selective antagonists of the serotonin 5-HT6 receptor. , 2010, Journal of medicinal chemistry.

[40]  B. Roth,et al.  The medicinal chemistry of 5-HT6 receptor ligands with a focus on arylsulfonyltryptamine analogs. , 2010, Current topics in medicinal chemistry.

[41]  Jessica Sallander,et al.  Benzimidazole derivatives as new serotonin 5-HT6 receptor antagonists. Molecular mechanisms of receptor inactivation. , 2010, Journal of medicinal chemistry.

[42]  C. González-Espinosa,et al.  Time-course of 5-HT6 receptor mRNA expression during memory consolidation and amnesia , 2010, Neurobiology of Learning and Memory.

[43]  G. Rosse,et al.  5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. , 2010, Current topics in medicinal chemistry.

[44]  John Dunlop,et al.  Neuronal nicotinic acetylcholine receptors - targets for the development of drugs to treat cognitive impairment associated with schizophrenia and Alzheimer's disease. , 2010, Current topics in medicinal chemistry.

[45]  V. R. Marcy,et al.  Activation of the 5-HT6 receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus , 2009, Neuroscience.

[46]  Christina A. Wilson,et al.  Enhancing cognition in neurologic disorders: Potential usefulness of 5-HT6 antagonists , 2009, Drugs of the Future.

[47]  Michael J Marino,et al.  Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. , 2009, Biochemical pharmacology.

[48]  J. Holenz,et al.  Identification of novel indanylsulfonamide guanylhydrazones as potent 5-HT6 serotonin receptor antagonists. , 2009, Journal of medicinal chemistry.

[49]  W. Geldenhuys,et al.  The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer’s disease , 2009, Expert review of neurotherapeutics.

[50]  L. W. Cooke,et al.  Synthesis and SAR of tolylamine 5-HT6 antagonists. , 2009, Bioorganic & medicinal chemistry letters.

[51]  A. Robichaud,et al.  5‐HT6 antagonists as potential treatment for cognitive dysfunction , 2009 .

[52]  David B. Sattelle,et al.  Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection , 2009, Pharmacological Reviews.

[53]  M. Shahid,et al.  Asenapine: a novel psychopharmacologic agent with a unique human receptor signature , 2009, Journal of psychopharmacology.

[54]  K. Fone.  An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function , 2008, Neuropharmacology.

[55]  F. Gil-Bea,et al.  Effects of 5‐HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat , 2008, British journal of pharmacology.

[56]  Charles A. Marsden,et al.  A role for the 5-HT1A, 5-HT4 and 5-HT6 receptors in learning and memory , 2008 .

[57]  W. Geldenhuys,et al.  Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease. , 2008, Current topics in medicinal chemistry.

[58]  M. Sano,et al.  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 , 2008, The Lancet.

[59]  T. Comery,et al.  A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands. , 2008, Bioorganic & medicinal chemistry letters.

[60]  Neil Upton,et al.  5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease , 2008, Neurotherapeutics.

[61]  Derek Cole,et al.  Neuropharmacological Profile of Novel and Selective 5-HT6 Receptor Agonists: WAY-181187 and WAY-208466 , 2008, Neuropsychopharmacology.

[62]  X. Codony,et al.  Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders. , 2008, Pharmacology & therapeutics.

[63]  B. Roth,et al.  Binding of serotonin and N1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies. , 2008, Journal of medicinal chemistry.

[64]  Jae Yang Kong,et al.  Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists. , 2008, Bioorganic & medicinal chemistry letters.

[65]  G. Bernardi,et al.  Endogenous Serotonin Excites Striatal Cholinergic Interneurons via the Activation of 5-HT 2C, 5-HT6, and 5-HT7 Serotonin Receptors: Implications for Extrapyramidal Side Effects of Serotonin Reuptake Inhibitors , 2007, Neuropsychopharmacology.

[66]  J. Neumaier,et al.  Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning , 2007, Neuropsychopharmacology.

[67]  D. Misner,et al.  3,4-Dihydro-2H-benzo[1,4]oxazine derivatives as 5-HT6 receptor antagonists. , 2007, Bioorganic & medicinal chemistry letters.

[68]  R. Schreiber,et al.  Effects of the novel 5-HT6 receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating , 2007, European Neuropsychopharmacology.

[69]  J. Baik,et al.  The Novel Cellular Mechanism of Human 5-HT6 Receptor through an Interaction with Fyn* , 2007, Journal of Biological Chemistry.

[70]  C. Regan,et al.  SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. , 2006, European journal of pharmacology.

[71]  B. Roth,et al.  Interaction of N1-unsubstituted and N1-benzenesulfonyltryptamines at h5-HT6 receptors. , 2006, Bioorganic & medicinal chemistry letters.

[72]  M. Garcia-Alloza,et al.  Lack of localization of 5‐HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5‐HT6 receptor‐mediated acetylcholine release , 2006, The European journal of neuroscience.

[73]  B. Roth,et al.  Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors. , 2006, Journal of medicinal chemistry.

[74]  J. Holenz,et al.  Medicinal chemistry strategies to 5-HT(6) receptor ligands as potential cognitive enhancers and antiobesity agents. , 2006, Drug discovery today.

[75]  J. Neumaier,et al.  5-HT6 receptors: a novel target for cognitive enhancement. , 2005, Pharmacology & therapeutics.

[76]  Michael A. Briggs,et al.  Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists. , 2005, Bioorganic & medicinal chemistry letters.

[77]  A. Meneses,et al.  Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task , 2005, Pharmacology Biochemistry and Behavior.

[78]  Leonardo Pardo,et al.  A three-dimensional pharmacophore model for 5-hydroxytryptamine6 (5-HT6) receptor antagonists. , 2005, Journal of medicinal chemistry.

[79]  V. Brown,et al.  5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats , 2005, Psychopharmacology.

[80]  J. Holenz,et al.  Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands. , 2005, Journal of medicinal chemistry.

[81]  V. Setola,et al.  1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands. , 2005, Bioorganic & medicinal chemistry letters.

[82]  J. Ellingboe,et al.  Discovery of 5-arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent, selective 5-HT6 receptor agonists and antagonists. , 2005, Journal of medicinal chemistry.

[83]  J. Ellingboe,et al.  N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are potent and selective 5-HT6 receptor antagonists. , 2005, Bioorganic & medicinal chemistry letters.

[84]  R. Glennon,et al.  Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors. , 2004, Bioorganic & medicinal chemistry letters.

[85]  A. Sleight,et al.  5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation—an effect sensitive to NMDA receptor antagonism , 2004, Neuropharmacology.

[86]  J. Standridge.  Pharmacotherapeutic approaches to the treatment of Alzheimer's disease. , 2004, Clinical therapeutics.

[87]  M. Garcia-Alloza,et al.  Differential Involvement of 5-HT1B/1D and 5-HT6 Receptors in Cognitive and Non-cognitive Symptoms in Alzheimer's Disease , 2004, Neuropsychopharmacology.

[88]  C. Marsden,et al.  5-ht6 receptors. , 2004, Current drug targets. CNS and neurological disorders.

[89]  V. Setola,et al.  Why mice are neither miniature humans nor small rats: a cautionary tale involving 5-hydroxytryptamine-6 serotonin receptor species variants. , 2003, Molecular pharmacology.

[90]  G. W. Price,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. , 2003, Molecular pharmacology.

[91]  V. Gribkoff,et al.  An Assessment of the Effects of Serotonin 6 (5-HT6) Receptor Antagonists in Rodent Models of Learning , 2003, Journal of Pharmacology and Experimental Therapeutics.

[92]  A. Sleight,et al.  Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro 04-6790 , 2003, Psychopharmacology.

[93]  S. Nawoschik,et al.  Characterization of the 5-HT6 receptor coupled to Ca2+ signaling using an enabling chimeric G-protein. , 2003, European journal of pharmacology.

[94]  T. Myhrer.  Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks , 2003, Brain Research Reviews.

[95]  M. Bös,et al.  Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. , 2003, Journal of medicinal chemistry.

[96]  G. Bernardi,et al.  Association study of the 5-hydroxytryptamine6 receptor gene in Alzheimer's disease , 2002, Neuroscience Letters.

[97]  R. Dias,et al.  Memories are made of this (perhaps): a review of serotonin 5-HT(6) receptor ligands and their biological functions. , 2002, Current topics in medicinal chemistry.

[98]  S. Bromidge,et al.  Bicyclic piperazinylbenzenesulphonamides are potent and selective 5-HT6 receptor antagonists. , 2002, Bioorganic & medicinal chemistry letters.

[99]  A. Slassi,et al.  Recent progress in 5-HT6 receptor antagonists for the treatment of CNS diseases , 2002 .

[100]  J. Hagan,et al.  5-HT6 receptor antagonists enhance retention of a water maze task in the rat , 2001, Psychopharmacology.

[101]  L. Dawson,et al.  The 5-HT6 Receptor Antagonist SB-271046 Selectively Enhances Excitatory Neurotransmission in the Rat Frontal Cortex and Hippocampus , 2001, Neuropsychopharmacology.

[102]  M. Knowles,et al.  N-Arylsulfonylindole derivatives as serotonin 5-HT(6) receptor ligands. , 2001, Journal of medicinal chemistry.

[103]  A. Sleight,et al.  A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze , 2001, Neuropharmacology.

[104]  A. Meneses.  Effects of the 5-HT6 receptor antagonist Ro 04-6790 on learning consolidation , 2001, Behavioural Brain Research.

[105]  S. Bromidge,et al.  Phenyl benzenesulfonamides are novel and selective 5-HT6 antagonists: identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134). , 2001, Bioorganic & medicinal chemistry letters.

[106]  B. Roth,et al.  N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists. , 2000, Bioorganic & medicinal chemistry letters.

[107]  D. Middlemiss,et al.  Characterization of SB‐271046: A potent, selective and orally active 5‐HT6 receptor antagonist , 2000, British journal of pharmacology.

[108]  D. Middlemiss,et al.  Characterization of [125I]‐SB‐258585 binding to human recombinant and native 5‐HT6 receptors in rat, pig and human brain tissue , 2000 .

[109]  B. Roth,et al.  2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors. , 2000, Journal of medicinal chemistry.

[110]  S. Tsai,et al.  Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer's disease , 1999, Neuroscience Letters.

[111]  A. Brown,et al.  5-Chloro-N-(4-methoxy-3-piperazin-1-yl- phenyl)-3-methyl-2-benzothiophenesulfon- amide (SB-271046): a potent, selective, and orally bioavailable 5-HT6 receptor antagonist. , 1999, Journal of medicinal chemistry.

[112]  F. Monsma,et al.  Identification of Residues in Transmembrane Regions III and VI that Contribute to the Ligand Binding Site of the Serotonin 5‐HT6 Receptor , 1998, Journal of neurochemistry.

[113]  A. Sleight,et al.  Characterization of Ro 04‐6790 and Ro 63‐0563: potent and selective antagonists at human and rat 5‐HT6 receptors , 1998, British journal of pharmacology.

[114]  F. Monsma,et al.  Interaction of tryptamine and ergoline compounds with threonine 196 in the ligand binding site of the 5-hydroxytryptamine6 receptor. , 1997, Molecular pharmacology.

[115]  L. Lanfumey,et al.  Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system , 1997, Brain Research.

[116]  M. Martres,et al.  Quantitative RT‐PCR distribution of serotonin 5‐HT6 receptor mRNA in the central nervous system of control or 5,7‐dihydroxytryptamine‐treated rats , 1996, Synapse.

[117]  D. Sibley,et al.  Cloning, Characterization, and Chromosomal Localization of a Human 5‐HT6 Serotonin Receptor , 1996, Journal of neurochemistry.

[118]  F. Monsma,et al.  Determination of the role of the 5-ht6 receptor in the rat brain: a study using antisense oligonucleotides. , 1995, The Journal of pharmacology and experimental therapeutics.

[119]  J. Bockaert,et al.  5-HT6 receptors positively coupled to adenylyl cyclase in striatal neurones in culture. , 1994, Neuroreport.

[120]  D. Sibley,et al.  Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. , 1994, The Journal of pharmacology and experimental therapeutics.

[121]  J. Schwartz,et al.  A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. , 1993, Biochemical and biophysical research communications.

[122]  D. Sibley,et al.  Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. , 1993, Molecular pharmacology.

[123]  D. Marazziti,et al.  Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology. , 2013, Current medicinal chemistry.

[124]  A. Meneses,et al.  5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes. , 2011, International review of neurobiology.

[125]  A. Robichaud,et al.  5-HT6 medicinal chemistry. , 2010, International review of neurobiology.

[126]  Hyunah Choo,et al.  New Serotonin 5-HT6 Ligands from Common Feature Pharmacophore Hypotheses , 2008, J. Chem. Inf. Model..

[127]  X. Guitart,et al.  Drug discovery targets: 5-HT6 receptor , 2005 .

[128]  K. J. Murphy,et al.  The 5-HT6 Receptor Antagonist SB-271046 Reverses Scopolamine-Disrupted Consolidation of a Passive Avoidance Task and Ameliorates Spatial Task Deficits in Aged Rats , 2004, Neuropsychopharmacology.

[129]  P. Scheltens,et al.  Treatment of Alzheimer's disease: current status and new perspectives. , 2003, The Lancet. Neurology.