Selective 5-hydroxytryptamine3 (5-HT3) receptor blocking activity of KB-R6933, a novel benzimidazole derivative.

: 5-Hydroxytryptamine3 (5-HT3)-receptor blocking activities of KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) were assessed in vivo and in vitro. Intravenous administration of KB-R6933, granisetron, ondansetron and azasetron inhibited 5-HT-induced bradycardia (von Bezold-Jarisch reflex) in anesthetized rats, with ED50 values of 0.071, 0.71, 4.0 and 0.82 microg/kg, respectively. The inhibitory effect of KB-R6933 at a dose of 0.3 microg/kg lasted for at least 8 hr, whereas those of granisetron at 30 microg/kg, ondansetron at 100 microg/kg and azasetron at 30 microg/kg nearly disappeared within 2-4 hr. Oral administration of KB-R6933 and granisetron also inhibited the bradycardia, with ED50 values of 0.41 and 76.3 microg/kg, respectively. In guinea pig ileum, KB-R6933 concentration-dependently antagonized 5-HT-evoked contraction and reduced the maximal contraction (pK(B)=8.75). Granisetron, ondansetron and azasetron shifted the dose-response curve for 5-HT to higher concentrations with no reduction of maximal contraction, and their pK(B)s were 7.65, 7.00 and 6.29, respectively. In a radioligand receptor binding study, KB-R6933, granisetron, ondansetron and azasetron displaced [3H]GR65630 binding to rat entorhinal cortex membrane, with Ki values of 0.066, 0.99, 2.70 and 2.5 nM, respectively. On the other hand, KB-R6933 exhibited negligible affinities for other receptors or binding sites tested, except for a weak affinity for the cholinergic M1-receptor, even at concentrations up to 10 microM. These results suggest that KB-R6933 is a potent and selective 5-HT3-receptor antagonist with a longer duration of action than those of existing 5-HT3-receptor antagonists.