Akio Ozaki, Yuko Fujishima and Takayuki Sukamoto
Pharmaceuticals R&D Center, Kanebo, Ltd., 1-5-90, Tomobuchi-cho,
Miyakojima-ku, Osaka 534-8666, Japan
Abstract: 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 (pKB=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 pKBs 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.
Keywords: KB-R6933, Benzimidazole derivative, 5-HT3-receptor
antagonist, von Bezold-Jarisch reflex, [3H]GR65630 binding