1276 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 7
Brief Articles
(9) Bourson, A.; Borroni, E.; Austin, R. H.; Monsma, F. J ., J r.;
Sleight, A. J . Determination of the Role of the 5-HT6 Receptor
in the Rat Brain: a Study Using Antisense Oligonucleotides. J .
Pharmacol. Exp. Ther. 1995, 274, 173-180.
(10) Bentley, J . C.; Bourson, A.; Boess, F. G.; Fone, K. C. F.; Marsden,
C. A.; Petit, N.; Sleight, A. J . Investigation of Stretching
Behavior Induced by the Selective 5-HT6 Receptor Antagonist,
Ro 04-6790, in Rats. Br. J . Pharmacol. 1999, 126, 1537-1542.
(11) Sleight, A. C.; Boess, F. G.; Bo¨s, M.; Levet-Trafit, B.; Riemer,
C.; Bourson, A. Characterization of Ro 04-6790 and Ro 63-0563:
Potent and Selective Antagonists at Human and Rat 5-HT6
Receptors. Br. J . Pharmacol. 1998, 124, 556-562.
(12) Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson, K.; Gager,
T.; Grassam, H. L.; J effrey, P. M.; J oiner, G. F.; King, F. D.;
Middlemiss, D. N.; Moss, S. F.; Newman, H.; Riley, G.; Rout-
ledge, C.; Wyman, P. 5-Chloro-N-(4-methoxy-3-piperazin-1-yl-
phenyl)-3-methyl-2-benzothiophene-sulfonamide (SB-271046): A
Potent, Selective and Orally Bioavailable 5-HT6 Receptor An-
tagonist. J . Med. Chem. 1999, 42, 202-205.
(13) Bromidge, S. M.; Clarke, S. E.; King, F. D.; Lovell, P. J .;
Newman, H.; Riley, G.; Routledge, C.; Serafinowska, H.; Smith,
D. R.; Thomas, D. R. Bicyclic Piperazinylbenzenesulfonamides
are Potent and Selective 5-HT6 Receptor Antagonists. Bioorg.
Med. Chem. Lett. 2002, 12, 1357-1360.
(14) Glennon, R. A.; Lee, M.; Rangisetty, J . B.; Dukat, M.; Roth, B.
L.; Savage, J . E.; McBride, A.; Rauser, L.; Hufeisen, S.; Lee, D.
K. H. 2-Substituted Tryptamines: Agents with Selectivity for
the 5-HT6 Serotonin Receptors. J . Med. Chem. 2000, 43, 1011-
1018.
(15) Russell, M. G. N.; Baker, R. J .; Barden, L.; Beer, M. S.; Bristow,
L.; Broughton, H. B.; Knowles, M.; McAllister, G.; Patel, S.;
Castro, J . L. N-Arylsulfonylindole Derivatives as Serotonin
5-HT6 Receptor Ligands. J . Med. Chem. 2001, 44, 3881-3895.
(16) (a) Reavill, C.; Rogers, D. C. The Therapeutic Potential of 5-HT6
Receptor Antagonists. Curr. Opin. Invest. Drugs 2001, 2, 104-
109. (b) Slassi, A.; Isaac, M.; O’Brien, A. Recent Progress in
5-HT6 Receptor Antagonists for the Treatment of CNS Diseases.
Expert Opin. Ther. Pat. 2002, 12, 513-527. (c) Russell, M. G.
N.; Dias, R. Memories are Made of This (Perhaps): A Review of
Serotonin 5-HT6 Receptor Ligands and Their Biological Func-
tions. Curr. Topics Med. Chem. 2002, 2, 643-654.
F igu r e 4. Reversal of a scopolamine (SCO)-induced retention
deficit in a passive avoidance task by repeated daily oral
administration of either compound 11 (solid bar) or donepezil
(DON) in comparison with vehicle (VEH).
for 5-HT6 receptor antagonists for the treatment of
memory disorders.
Ack n ow led gm en t. The authors thank Mr. B. Wag-
ner and F. Senner for log D, solubility and pKa deter-
minations, Mr. M. Kapps and Mrs. M. S. Gruyer for the
analysis of and the PK in vivo experiments, Mr. H.
Ehrsam for the microdialysis, Dr. Andrew Sleight, Mrs.
C. Carolo, and Mr. A. Rudler for the in vitro binding,
Catherine Diener and Christophe Fischer for the cAMP
data, Ms. F. Kahn, Ms. B. Algeyer, and Ms. S. Sa¨nger
for their technical assistance in conducting the behav-
ioral experiments and Mr. B. Hofstetter for his skillful
synthetic contributions.
(17) Dawson, L. A.; Nguyen, H. Q.; Li, P. In Vivo Effects of the 5-HT6
Antagonist SB-271046 on Striatal and Frontal Cortex Extra-
cellular Concentrations of Noradrenaline, Dopamine, 5-HT,
Glutamate and Aspartate. Br. J . Pharmacol. 2000, 130, 23-26.
(18) Dawson, L. A.; Nguyen, H. Q.; Li, P. The 5-HT6 Receptor
Antagonist SB-271046 Selectively Enhances Excitatory Neu-
rotransmission in the Rat Frontal Cortex and Hippocampus.
Neuropsychopharmacology 2001, 25, 662-668.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral characterization data for compounds 2
and 10-12 are available free of charge via the Internet at
http://pubs.acs.org.
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Transgenic Mice Expressing Apolipoprotein E4(C112R) and
Apolipoprotein E4(L28P; C112R). Neuroscience 2000, 101, 211-
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