AbstractRG 12915, N‐(1‐azabicyclo[2.2.2.]octan‐3(S)‐yl)‐2‐chloro‐(5aS, 9aS)‐5a,6,7,8,9,9a‐hexahydrodibenzofuran‐4‐carboxamide, a potent antiemetic agent active in reducing emesis produced by antieoplastic agents, was examined in tests of 5‐hydroxytryptamine3(5‐HT3) receptor blockade. RG 12915 was found to be a potent antagonist of 5‐HT3receptor activation both in blocking 5‐HT‐induced contractions of guinea‐pig ileum and in blocking the Bezold‐Jarisch effect in the rat. Compared to several other 5‐HT3antagonists, RG 12915 had a greater pA2 value (11.2) for blocking 5‐HT‐induced contractions of guinea pig ileum than zacopride (8.3); BRL 43694 (granisetron) (9.1); and GR 38032F (ondansetron) (7.4). Falls in heart rate due to 5‐HT3receptor activation following intravenous (i.v.) administration of 5‐HT (the Bezold‐Jarisch effect) were also potently reduced by RG 12915. Minimum effective dose (MED) levels (in parentheses), defined as the lowest dose at which each compound produced a significant reduction in the Bezold‐Jarisch effect, were determined for RG 12915 (1.0μg/kg, i.v.); zacopride (3.0); granisetron (9.0); and ondansetron (27.0). The order of potency in blocking 5‐HT3receptor activation was generally the same as the order of potency in 5‐HT3receptor binding. RG 12915 had a lower Kivalue (0.17±0.02 nM, mean ± SEM) in binding studies using3H‐GR‐65630 as the ligand in rat entorhinal cortex tissue than either zacopride (1.5±0.4); granisetron (1.7±0.3); or ondansetron (6.2±2.1). RG 12915 was also found active in blocking contractions of guinea pig ileum and the Bezold‐Jarisch effect induced by the somewhat selective 5‐HT3receptor agonist 2‐methyl‐secrotonin. The results support the idea that this orally active antiemetic agent is