The indole derivative SB-207266 is a selective and potent antagonist of the serotonin (5-HT) receptor 5-HT4 with a pA2 value of 10.6 ± 0.1. In COS7 cells, 100 nM SB-207266 inhibited 5-HT4 responses to 5-HT and reduced basal agonist-independent cAMP production. In several animal models, low concentrations of SB-207266 blocked exogenous 5-HT-mediated sensitization of intestinal peristalsis. In a dog model, SB-207266 (0.1–100 pg/kg) dose-dependently reduced responses to 5-HT, with an ID50 value of 1.3 pg/kg. SB-206226 (0.5 mg/kg/24 h) improved cardiac function in a rat model of congestive heart failure.