Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist.
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
Cole
Derek C
DC
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. coledc@wyeth.com
Stock
Joseph R
JR
Lennox
William J
WJ
Bernotas
Ronald C
RC
Ellingboe
John W
JW
Boikess
Steve
S
Coupet
Joseph
J
Smith
Deborah L
DL
Leung
Louis
L
Zhang
Guo-Ming
GM
Feng
Xidong
X
Kelly
Michael F
MF
Galante
Rocco
R
Huang
Pingzhong
P
Dawson
Lee A
LA
Marquis
Karen
K
Rosenzweig-Lipson
Sharon
S
Beyer
Chad E
CE
Schechter
Lee E
LE
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005625:Frontal Lobe / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D017551:Microdialysis; D008862:Microsomes, Liver / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014363:Tryptamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C525454:N(1)-(6-chloroimidazo(2,1-b)(1,3)thiazole-5-sulfonyl)tryptamine; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D014363:Tryptamines; C097216:serotonin 6 receptor; D005680:gamma-Aminobutyric Acid