The serotonin 5-HT4 receptor. 2. Structure-activity studies of the indole carbazimidamide class of agonists.
A number of substituted indole carbazimidamides were prepared and evaluated as 5-HT4 receptor agonists by using the isolated field-stimulated guinea pig ileum preparation. Their selectivity for the 5-HT4 receptor was established by examining their affinity for other 5-HT receptors using radioligand-binding techniques. Several selective and highly potent full as well as partial agonists emerged from this study. For example, 1b,d were found to be the most potent, full 5-HT4 receptor agonist described so far (EC50 = 0.5 and 0.8 nM, respectively), being 6 and 4 times more potent than serotonin itself. On the other hand, 5b and 1h appeared as partial 5-HT4 receptor agonists in the nonstimulated guinea pig ileum preparation with potencies, evaluated against serotonin action, respectively similar (5b, Ki = 12 nM) to and 300-fold higher (1h, Ki = 0.04 nM) than serotonin.
Buchheit
K H
KH
Sandoz Pharma Limited, Basel, Switzerland.
Gamse
R
R
Giger
R
R
Hoyer
D
D
Klein
F
F
Klöppner
E
E
Pfannkuche
H J
HJ
Mattes
H
H
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D000577:Amides; D007211:Indoles; D017366:Serotonin Receptor Agonists