Selective 5-Hydroxytryptamine_3 (5-HT_3) Receptor Blocking Activity of KB-R6933, a Novel Benzimidazole Derivative

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5-Hydroxytryptamine<SUB>3</SUB> (5-HT<SUB>3</SUB>)-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 ED<SUB>50</SUB> values of 0.071, 0.71, 4.0 and 0.82 μg/kg, respectively. The inhibitory effect of KB-R6933 at a dose of 0.3 μg/kg lasted for at least 8 hr, whereas those of granisetron at 30 μg/kg, ondansetron at 100 μg/kg and azasetron at 30 μg/kg nearly disappeared within 2 - 4 hr. Oral administration of KB-R6933 and granisetron also inhibited the bradycardia, with ED<SUB>50</SUB> values of 0.41 and 76.3 μg/kg, respectively. In guinea pig ileum, KB-R6933 concentration-dependently antagonized 5-HT-evoked contraction and reduced the maximal contraction (pK<SUB>B</SUB>=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<SUB>B</SUB>s were 7.65, 7.00 and 6.29, respectively. In a radioligand receptor binding study, KB-R6933, granisetron, ondansetron and azasetron displaced [<SUP>3</SUP>H]GR65630 binding to rat entorhinal cortex membrane, with K<SUB>i</SUB> 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 M<SUB>1</SUB>-receptor, even at concentrations up to 10 μM. These results suggest that KB-R6933 is a potent and selective 5-HT<SUB>3</SUB>-receptor antagonist with a longer duration of action than those of existing 5-HT<SUB>3</SUB>-receptor antagonists.


  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 80(1), 25-32, 1999-05-01

    The Japanese Pharmacological Society

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