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 eval uated as 5-HT4 receptor agonists by using the isolated field-stimulate d guinea pig ileum preparation. Their selectivity for the 5-HT4 recept or was established by examining their affinity for other 5-HT receptor s using radioligand-binding techniques. Several selective and highly p otent full as well as partial agonists emerged from this study. For ex ample, 1b,d were found to be the most potent, full 5-HT4 receptor agon ists described so far (EC(50) = 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 nonstimulate d guinea pig ileum preparation with potencies, evaluated against serot onin action, respectively similar (5b, K-i = 12 nM) to and 300-fold hi gher (1h, K-i = 0.04 nM) than serotonin.