Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents (DOI:10.1016/j.drudis.2006.02.004);Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents

Drug Discovery Today

Volumn 11, Issue 7-8, 2006, Pages 283-299

  Holenz, Jörg ^a   Pauwels, Petrus J ^a   Díaz, José Luis ^a   Mercè, Ramon ^a   Codony, Xavier ^a   Buschmann, Helmut ^a  

^a Laboratorios Dr Esteve SA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

1 BENZENESULFONYL 5 METHOXY N,N DIMETHYLTRYPTAMINE; 4 AMINO N [2,6 BIS(METHYLAMINO) 4 PYRIDINYL]BENZENESULFONAMIDE; 4 AMINO N [2,6 BIS(METHYLAMINO) 4 PYRIMIDINYL]BENZENESULFONAMIDE; 5 CHLORO N [4 METHOXY 3 (1 PIPERAZINYL)PHENYL] 3 METHYL 2 BENZOTHIOPHENESULFONAMIDE; ALX 0440; ALX 1161; ALX 1175; AMITRIPTYLINE; ANTIOBESITY AGENT; ANTISENSE OLIGONUCLEOTIDE; ATYPICAL ANTIPSYCHOTIC AGENT; BVT 5182; CHOLINESTERASE INHIBITOR; CLOZAPINE; DONEPEZIL; GSK 215083; LY 483518; MIANSERIN; NOOTROPIC AGENT; RO 43 68554; RO 65 7199; RO 65 7674; RO 66 0074; SAX 187; SB 214111; SB 258510; SB 357134; SB 399885; SB 699929; SB 742457; SEROTONIN 2C AGONIST; SEROTONIN 6 ANTAGONIST; SEROTONIN 6 RECEPTOR; SEROTONIN ANTAGONIST; SGS 518; UNCLASSIFIED DRUG; UNINDEXED DRUG; WAY 181187; WAY 466;

ALZHEIMER DISEASE; ANXIETY; BINDING AFFINITY; CLINICAL TRIAL; COGNITION; COGNITIVE DEFECT; DOSE RESPONSE; DRUG RECEPTOR BINDING; DRUG TARGETING; GENETIC POLYMORPHISM; HUMAN; LEARNING; MEMORY; MEMORY CONSOLIDATION; MEMORY DISORDER; MOOD DISORDER; NEUROTRANSMISSION; NONHUMAN; OBESITY; PHARMACOPHORE; RECEPTOR DOWN REGULATION; REVIEW; SCHIZOPHRENIA; STRAIN DIFFERENCE; STRUCTURE ACTIVITY RELATION; TASK PERFORMANCE;

EID: 33645880762     PISSN: 13596446     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.drudis.2006.04.002     Document Type: Erratum

References (137)

1. Monsma F.J., et al. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol. Pharmacol. 43 (1993) 320-327
2. Unsworth C.D., and Molinoff P.B. Characterization of a 5-hydroxytryptamine receptor in mouse neuroblastoma N18TG2 cells. J. Pharmacol. Exp. Ther. 269 (1994) 246-255
3. Kohen R., et al. Cloning, characterisation, and chromosomal location of human 5-HT6 serotonin receptor. J. Neurochem. 66 (1996) 47-56
4. Sebben M., et al. 5-HT6 receptors positively coupled to adenylyl cyclase in striatal neurones in culture. Neuroreport 5 (1994) 2553-2557
5. Woolley M.L., et al. 5-ht6 receptors. Curr Drug Targets CNS Neurol Disord. 3 (2004) 59-79
6. Davies S.L., et al. Drug discovery targets: 5-HT6 receptor. Drugs of the Future 30 (2005) 479-495
7. Tecott, L.H. and Brennan, T.J. (2000) Serotonin 5-HT6 receptor knockout mouse. US patent 6,060,642.
8. Hirst W.D., 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 (2003) 1295-1308
9. Setola V., and Roth B.L. Why mice are neither miniature humans nor small rats: A cautionary tale involving 5-Hydroxytyptamine-6 serotonin receptor species variants. Mol. Pharmacol. 64 (2003) 1277-1278
10. Sleight A.J., et al. 5-HT6 and 5-HT7 receptors: molecular biology, functional correlates and possible therapeutic indications. Drug News Perspect. 10 (1997) 214-224
11. Fredericks J.A., and Woodruff J.H. Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in the rat brain. Schizophr. Res. 38 (1999) 7-12
12. Yu Y.W., et al. Serotonin-6 receptor variant (C267T) and clinical response to clozapine. Neuroreport 10 (1999) 1231-1233
13. Masellis M., et al. Lack of association between the T → C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophr. Res. 47 (2001) 49-58
14. Pouzet B., et al. Effects of the 5-HT (6) receptor antagonist, SB-271046, in animal models for schizophrenia. Pharmacol. Biochem. Behav. 71 (2002) 635-643
15. Kohen R., et al. Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop. Brain Res. Mol. Brain Res. 90 (2001) 110-117
16. Stean T., et al. Anticonvulsant properties of the selective 5-HT6 receptor antagonist SB-271046 in the rat maximal electroshock seizure threshold test. Br. J. Pharmacol. 127 (1999) 131P
17. Routledge C., et al. Characterization of SB-271046: a potent, selective and orally active 5-HT (6) receptor antagonist. Br. J. Pharmacol. 130 (2000) 1606-1612
18. King M.V., et al. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation -an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47 (2004) 195-204
19. Ennaceur A., and Delacour J. A new one-trial test for neurobiological studies of memory in rats. I: behavioural data. Behav. Brain Res. 31 (1988) 47-59
20. Prickaerts J., et al. Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation. Psychopharmacology (Berl.) 177 (2005) 381-390
21. Meneses A. Effects of the 5-HT6 receptor antagonist Ro 04-6790 on learning consolidation. Behav. Brain Res. 118 (2001) 107-110
22. Bentley J.C., et al. 5-HT6 antisense oligonucleotide i.c.v. affects rat performance in the water maze and feeding. J. Psychopharmacol. 11 (1997) A64
23. Woolley M.L., et al. A role for 5-HT6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 41 (2001) 210-219
24. Lieben C.K., et al. The selective 5-HT6 Receptor antagonist Ro 4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat. Neuropsychopharmacology 30 (2005) 2169-2179
25. Woolley M.L., 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. Psychopharmacology (Berl.) 170 (2003) 358-367
26. Sleight A.J., et al. 5-HT6 receptors: functional correlates and potential therapeutic indications. Behav. Pharmacol. 10 (1999) S86
27. Bös M., et al. 5-HT6 receptor antagonists: Lead optimisation and biological evaluation of N-aryl and N-heteroaryl 4-amino-benzene sulphonamides. Eur. J. Med. Chem. 36 (2001) 165-178
28. Riemer C., 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. J. Med. Chem. 46 (2003) 1273-1276
29. Rogers D.C., et al. Cognitive enhancement effects of the selective 5-HT6 antagonist SB-271046. Br. J. Pharmacol. 127 (1999) 22P
30. Perez-Garcia G., and Meneses A. Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task. Pharmacol. Biochem. Behav. 81 (2005) 673-682
31. Garcia-Alloza M., et al. Differential involvement of 5-HT1B/1D and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer's disease. Neuropsychopharmacology 29 (2004) 410-416
32. Rogers D.C., and Hagan J.J. 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology (Berl.) 158 (2001) 114-119
33. Van der Staay J., et al. Effects of metrifonate, its transformation product dichlorvos, and other organophosphorus and reference cholinesterase inhibitors on Morris water escape behavior in young-adult rats. J. Pharmacol. Exp. Ther. 278 (1996) 697-708
34. Braida D., et al. An inverted U-shaped curve for heptylphysostigmine on radial maze performance in rats: comparison with other cholinesterase inhibitors. Eur. J. Pharmacol. 302 (1996) 13-20
35. Cheng D.H., et al. Huperzine-A, a novel promising acetyl-cholinesterase inhibitor. Neuroreport 8 (1996) 97-101
36. Ohara T., et al. SDZ ENA 713 facilitates central cholinergic function and ameliorates spatial memory impairment in rats. Behav. Brain Res. 83 (1997) 229-233
37. Foley A.G., et al. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology 29 (2004) 93-100
38. Stean T.O., et al. Pharmacological profile of SB-357134: A potent, selective, brain penetrant, and orally active 5-HT6 receptor antagonist. Pharmacol. Biochem. Behav. 71 (2002) 645-654
39. Hatcher P.D., et al. 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. Psychopharmacology (Berl.) 181 (2005) 253-259
40. Lindner M.D., et al. An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning. J. Pharmacol. Exp. Ther. 307 (2003) 682-691
41. Saegis, (2005) Saegis pharmaceutical completes phase IIa clinical study of SGS518. Saegis Press Release, December 15.
42. Information on structure class and clinical status from Integrity database, Prous Science, and from Investigational Drugs Database IDdb3, Thomson Current Drugs, and from http://www.newhealth.govt.nz/ethicscommittees/committees/agenda-and-minutes/multi-region/17may05/mec-minutes-17may2005.doc.
43. Vickers S.P., and Dourish C.T. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs 5 (2004) 377-388
44. Caldirola, P. (2003) 5-HT6 receptor antagonism: A novel mechanism for the management of obesity. SMI Conf. obesity and related disorders (Feb. 17-18, London).from: www.iddb3.com.
45. Bentley J.C., et al. Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist Ro 04-6790 in rats. Br. J. Pharmacol. 126 (1999) 1537-1542
46. Svartengren, J. et al. (2003) The serotonin 5-HT6 receptor antagonist BVT-5182 reduces body weight of high fat diet-induced mice, Int. J. Obes. 27, Suppl.1. Abst T1, 1-094.
47. Svartengren, J. et al. (2004) The selective serotonin 5-HT6 receptor antagonist BVT-5182 decreases food intake and body weight in both rats and mice. 34th Annu. Meet. Soc. Neurosci. Abstract 75.8.
48. Jossan, S. et al. (2002) Formulations comprising a 5-HT agonist and 5-HT6 antagonist useful for the treatment of obesity. WO patent 2002008178.
49. Slassi A., et al. Recent progress in 5-HT6 receptor antagonists for the treatment for the CNS diseases. Expert Opin. Ther. Pat. 12 (2002) 513-527
50. Holenz J., et al. Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands. J. Med. Chem. 48 (2005) 1781-1795
51. Sleight A.J., et al. Characterization of Ro 04-6790 and Ro 63-0563: Potent and selective antagonists at human and rat 5-HT6 receptors. Br. J. Pharmacol. 124 (1998) 556-562
52. Bromidge S.M., et al. 5-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046): A potent, selective, and orally bioavailable 5-HT6 receptor antagonist. J. Med. Chem. 42 (1999) 202-205
53. Glennon R.A., et al. 5-HT6 serotonin receptor binding of indolealkylamines: A preliminary structure-affinity investigation. Med. Chem. Res. 9 (1999) 108-117
54. Glennon R.A., et al. 2-Substituted tryptamines: agents with selectivity for 5-HT6 serotonin receptors. J. Med. Chem. 43 (2000) 1011-1018
55. Tsai Y., et al. N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists. Bioorg. Med. Chem. Lett. 10 (2000) 2295-2299
56. Lee M., et al. 5-HT6 receptor serotonin receptor binding affinities of N1-benzenesulfonyl and related tryptamines. Med. Chem. Res. 10 (2000) 230-242
57. Glennon R.A., et al. Higher-end serotonin receptors: 5-HT5, 5-HT6, and 5-HT7. J. Med. Chem. 46 (2003) 2795-2812
58. Russell M.G.N., et al. N-Arylsulfonilindole derivatives as serotonin 5-HT6 receptor ligands. J. Med. Chem. 44 (2001) 3881-3895
59. Pullagurla M.R., et al. Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors. Bioorg. Med. Chem. Lett. 14 (2004) 4569-4573
60. Boess F.G., et al. Interaction of tryptamine and ergoline compounds with threonine 196 in the ligand binding site of the 5-hydroxytryptamine6 receptor. Mol. Pharmacol. 52 (1997) 515-523
61. Boess F.G., et al. Identification of residues in transmembrane regions III and VI that contribute to the ligand binding site of the serotonin 5-HT6 receptor. J. Neurochem. 71 (1998) 2169-2177
62. Boess F.G., et al. The 5-hydroxytryptamine6 receptor-selective radioligand [3H]Ro 63-0563 labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum. Mol. Pharmacol 54 (1998) 577-583
63. Doddareddy M.R., et al. Hologram quantitative structure activity relationship studies on 5-HT6 antagonists. Bioorg. Med. Chem. 12 (2004) 3815-3824
64. Doddareddy M.R., et al. CoMFA and CoMSIA 3D QSAR analysis on N1-arylsulfonylindole compounds as 5-HT6 antagonists. Bioorg. Med. Chem. 12 (2004) 3977-3985
65. Harris, R.N., III et al. (2004) Preparation of quinolinone and benzoxazinone derivatives as 5-HT6 modulators. WO patent 2004080969.
66. Maag, H. et al. (2004) Preparation of substituted benzoxazinones as selective 5-HT6 antagonists for treating central nervous system diseases and gastrointestinal tract disorders. US patent 2004092512.
67. Kolanos R., et al. Binding of isotryptamines and indenes at h5-HT6 serotonin receptors. Bioorg. Med. Chem. Lett. 15 (2005) 1987-1991
68. López-Rodríguez M.L., et al. A three-dimensional pharmacophore model for 5-hydroxytryptamine6 (5-HT6) receptor antagonists. J. Med. Chem. 48 (2005) 4216-4219
69. Bromidge S.M., 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). Bioorg. Med. Chem. Lett. 11 (2001) 55-58
70. Wu Y.-J., et al. Identification of a potent and selective 5-HT6 antagonist: One-step synthesis of (E)-3-(benzenesulfonyl)-2-(methylsulfonyl)pyrido[1,2-a]pyrimidin-4-ylidenamine from 2-(benzenesulfonyl)-3,3-bis(methylsulfanyl)acrylonitrile. J. Med. Chem. 46 (2003) 4834-4837
71. Cole D.C., et al. Conformationally constrained N1-arylsulfonyltryptamine derivatives as 5-HT6 receptor antagonists. Bioorg. Med. Chem. Lett. 15 (2005) 4780-4785
72. Aldridge S. Medicinal Chemistry Equals New Leads. Gen. Engineering News 25 (2005) 1
73. Cole, D.C. et al. (2003) Preparation of 1-(indol-3-yl)alkylidenehydrazine carboximidamides as 5-hydroxytryptamine-6 ligands. US patent 2003232843.
74. Cole D.C., et al. Discovery of 5-arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent, selective 5-HT6 receptor agonists and antagonists. J. Med. Chem. 48 (2005) 353-356
75. Schechter L.E., et al. WAY-466: In vitro and in vivo pharmacological characterization of a novel and selective 5-HT6 receptor agonist. Neuropsychopharmacology 29 Suppl. 1 (2004) S237
76. Spinks, D. et al. (2003) Preparation of 1-arylsulfonyl-3-substituted indoles and indolines for the treatment of central nervous system disorders. WO patent 2003068220.
77. Fu, J-M. (2003) Preparation of arylsulphonyl-substituted tetrahydro- and hexahydrocarbazolamines as 5-HT6 receptor ligands. WO patent 2003030901.
78. Chang-Fong J., et al. 1,2,3,4-Tetrahydrocarbazoles as 5-HT6 serotonin receptor ligands. Bioorg. Med. Chem. Lett. 14 (2004) 1961-1964
79. Cole, D.C. et al. (2005) Preparation of 3-[(hetero)arylsulfonyl]-tetrahydro-3H-benzo[e]indol-8-amines as 5-hydroxytryptamine-6 ligands. US patent 2005101596.
80. Cole, D.C. et al. (2005) Preparation of sulfonyldihydroimidazopyridinones as serotonin 5-HT6 ligands. WO patent 2005010003.
81. Greenblatt, L.P. (2005) Preparation of piperidinylchromenylsulfonamides as 5-HT6 ligands. WO patent 2005037830.
82. Johansson, G. et al. (2005) Preparation of benzofuran derivatives that can be used in prophylaxis or treatment of 5-HT6 receptor-related disorders like obesity. WO patent 2005058858.
83. Bernotas, R.C. et al. (2004) Preparation of heterocyclylalkyl-sulfonylazaindole or -azaindazole derivatives 5-hydroxytryptamine-6 (5-HT6) ligands. WO patent 2004009600.
84. Kelly, M.G. et al. (2003) Preparation of pyrrolylalkylidene-hydrazinecarboximidamides as 5-hydroxytryptamine-6 ligands. WO patent 2003068740.
85. Jasti, V. et al. (2005) Preparation of indeno[2,1-a]indenes and isoindol[2,1-a]indoles as modulators of 5HT receptors. WO patent 2005066184.
86. Hirst, W.D. et al. (2003) Characterisation of SB-399885, a potent and selective 5-HT6 receptor antagonist. 33rd Annu. Meet. Soc. Neurosci. (Nov. 8-12, New Orleans), Abstract 576.7; from: http://integrity.prous.com.
87. Medicinal Chemistry - XVIIIth International Symposium (Part V) (2004). Copenhagen, Denmark, and Malmoe, Sweden, http://www.iddb3.com.
88. MacDonald, G.J. et al. (2004) Preparation of novel phenyl sulfone derivatives and their use in the treatment of CNS disorders. WO patent 2004080986.
89. Tenbrink, R.E. et al. (2003) Preparation of pyridyl phenyl sulfones as 5-HT6 receptor modulators. WO patent 2003072548.
90. Stadler, H. et al. (1999) 5-HT6 antagonists: a novel approach fort he symptomatic treatment of Alzheimer's disease. 37th IUPAC Cong. (Aug14-19, Berlin), Abstract MM-7.
91. Bonhaus, D.W. et al. (2002) Ro-4368554, a high affinity, selective, CNS penetrating 5-HT6 receptor antagonist. 32nd Annu. Meet. Soc. Neurosci. (Nov 2-7, Orlando), Abstract 884.5.
92. Beard, C.C. et al. (2002) Preparation of new indole derivatives with 5-HT6 receptor affinity. WO patent 2002098857.
93. Berger, J. et al. (2003) Preparation of benzoxazines as 5-HT6 modulators. WO patent 2003095434.
94. Putman, D. (2004) Preparation of 2,5- and 2,6-substituted tetrahydroisoquinolines as 5-HT6 modulators, in particular selective 5-HT6 antagonists, for treating CNS disorders. WO patent 2004078176.
95. Madera, A.M. et al. (2004) Preparation of 2,4-substituted indoles as 5-HT6 modulators. WO patent 2004026831.
96. Bromidge, S.M. et al. (2002) Preparation of 4-piperazinoindoles for treating CNS disorders. WO patent 2002041889. Part of this work was later published in: Ahmed, M. et al. (2005) Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists. Bioorg. Med. Chem. Lett. 15, 4867-4871.
97. Johnson, C.N. et al. (2003) Preparation of arylsulfonylquinolinyl- of azaindolylpiperazines as 5-HT6 antagonists. WO patent 2003080608.
98. Ahmed, M. et al. (2003) Novel compounds. WO patent 2003080580.
99. Johnson, C.N. et al. (2005) Quinoline compounds and pharmaceutical compositions containing them. WO patent 2005026125.
100. A [11C] labeled compound is described: Martarello, L. et al. (2005) Radiolabelling and in vivo evaluation of [11C]GSK215083 as potential PET radioligand for the 5-HT6 receptor in the porcine brain. 7th Int. Conf. Quantification Brain Function PET (Jun 8-9, Amsterdam), Abstract BP-11; from: http://integrity.prous.com.
101. Bernotas, R.C. et al. (2004) Preparation of heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands. US patent 2004167122.
102. Kelly, M.G. et al. (2004) Preparation of 1-alkylsulfonylheterocyclylbenzazoles and related compounds as 5-hydroxytryptamine-6 ligands. US patent 2004192749.
103. Bernotas, R.C. et al. (2004) Heterocyclyl-3-sulfonylazaindole or-azaindazole derivatives as 5-HT6 receptor ligands, and their use for the treatment of central nervous system disorders. WO patent 2004074286.
104. Johansson, G. et al. (2004) Preparation of pyridino-fused heterocycles useful for the treatment of obesity, type II diabetes and CNS disorders. WO patent 2004000828.
105. Patent Alert (2003) from Current Opinion in Investigational Drugs 4, 911.
106. Torrens, A. et al. (2003) Compuestos sulfonamídicos derivados de benzoxazinona, su preparación y uso como medicamentos. ES patent Application 200301812.
107. Demchyshyn Ll. et al. (2001) ALX-1161: pharmacological properties of a potent and selective 5-HT6 receptor antagonist. 31st Annu. Meet. Soc. Neurosci. (Nov 10-15), Abstract 266.6; from: www.iddb3.com.
108. Mattsson, C. et al. (2002) Novel, potent and selective 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as 5-HT6 receptor agonists. XVIIth International Symposium on Medicinal Chemistry (Sep 1-5, Barcelona).
109. Mattsson C., et al. 2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists. Bioorg. Med. Chem. Lett. 15 (2005) 4230-4234
110. Mercè, R. et al. (2003) Derivatives of sulfonamides, their preparation and use as medicaments. WO patent 2003042175.
111. Cole, D.C. et al. (2003) Indolylalkylamine derivatives as 5-hydroxytryptamine-6-ligands. WO patent 2003053433.
112. Wang, Y. et al. (2006) Indolylalkylamine metabolites as 5-hydroxytryptamine-6-ligands. WO patent 2006002125.
113. Cole, D.C. et al. (2005) Discovery of a potent, selective and orally active 5-HT6 receptor agonist, WAY-181187. 230th ACS Natl. Meet. (Aug 28-Sept 1, Washington DC), Abstract MEDI 17.
114. Slassi, A. et al. (2000) Preparation of 1-(arylsulfonyl)-3-(tetrahydropyridinyl)indoles as 5-HT6 receptor inhibitors. WO patent 200063203.
115. Caldirola, P. (2003) Use of sulfonamide derivatives in the treatment of obesity or for the reduction of food intake. WO patent 2003039547.
116. Filla, S.A. et al. (2002) Preparation of benzenesulfonic acid indol-5-yl esters as antagonists of the 5-HT6 receptor. WO patent 2002060871.
117. Piñeiro-Núñez, M.M. et al. (2005) Discovery and SAR studies of 2,6-difluorobenzenesulfonic acid 1-methyl-3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester, a novel and potent 5-HT6 antagonist fort he treatment of cognitive deficit. 229th ACS Natl. Meet. (Mar 13-17, San Diego), Abstract MEDI 282.
118. Bernotas, R.C. et al. (2004) Preparation of 1-heterocyclylalkyl-3-sulfonylindoles and indazoles as 5-HT6 ligands. WO patent 2004009548.
119. Cole, D.C. et al. (2004) Preparation of indolylalkylidenehydrazine-carboximidamide derivatives as 5-hydroxytryptamine-6 ligands. US patent 2004002527.
120. Zhao, S-H. (2004) Preparation of aminoalkoxyindoles as 5-HT6-receptor ligands, in particular selective 5-HT6 antagonists, for treating CNS disorders. WO patent 2004050085.
121. Zhou P., et al. 4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands. Bioorg. Med. Chem. Lett. 15 (2005) 1393-1396
122. Abate C., et al. Interaction of chiral MS-245 analogs at h5-HT6 receptors. Bioorg. Med. Chem. Lett. 15 (2005) 3510-3513
123. Cole D.C., et al. N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are potent and selective 5-HT6 receptor antagonists. Bioorg. Med. Chem. Lett. 15 (2005) 379-383
124. Cole, D.C. (2005) Preparation of N-sulfonylheterocyclopyrrolylalkylamine compounds as 5-hydroxytryptamine-6 ligands. WO patent 2005012311.
125. Berger, J. et al. (2003) Preparation of 1-[2-alkoxy-5-(arylsulfonyl)phenyl]piperazines with 5-HT6 receptor affinity. WO patent 2003014097.
126. Tenbrink, R.E. et al. (2003) Preparation of arylsulfones as 5-HT6 receptor modulators. WO patent 2003072558.
127. Lee M., et al. 1-(1-Naphtyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands. Bioorg. Med. Chem. Lett. 15 (2005) 1707-1711
128. Bromidge, S.M. et al. (2003) Preparation of 7-arylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepines with 5-HT6 receptor affinity for the treatment of CNS disorders. WO patent 2003068751.
129. Wu, Y-J. et al. (2004) Preparation of pyridopyrimidines as 5-HT6 antagonists. US patent 2004019064.
130. Forbes, I.T. et al. (2005) Preparation of 7-phenylsulfonyl-tetrahydro-3-benzazepine derivatives as antipsychotic agents. WO patent 2005051398.
131. Leng A., et al. Effect of the 5-HT6 receptor antagonists Ro 04-6790 and Ro 65-7199 on latent inhibition and prepulse inhibition in the rat: comparison to clozapine. Pharmacol. Biochem. Behav. 75 (2003) 281-288
132. Dawson L.A., et al. The 5-HT6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology 25 (2001) 662-668
133. Dawson L.A., et al. In vivo effects of the 5-HT6 antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate. Br. J. Pharmaocol. 130 (2001) 23-26
134. Frantz K.J., et al. 5-HT6 receptor antagonism potentiates the behavioral and neurochemical effects of amphetamine but not cocaine. Neuropharmacology 42 (2002) 170-180
135. Minabe Y., et al. Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study. Synapse 52 (2004) 20-28
136. Pullagurla M., et al. Modulation of the stimulus effects of (+)-amphetamine by the 5-HT6 antagonist MS-245. Pharmacol. Biochem. Behav. 78 (2004) 263-268
137. Structure is most probably identical with the one protected as polymorph in: Galdwin, A. E. WO patent 2005040124.