The antagonistic activities of compound N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl 1H-indazole-3- carboxamide dihydrochlo ride) at 5-HT3 and 5-HT4 receptors were examined using in vitro and in vivo assays. N-3389 showed potent 5-HT3 receptor antagonistic activities in a radioligand binding assay (pKi = 8.77), against 2-methyl-5-HT (2-Me-5-HT)-induced bradycardia in rats (ED50 = 0.73 μg/kg i.v., 38 μg/kg p.o.) and against 2-Me-5-HT-induced contraction in longitudinal muscle myenteric plexus preparations of guinea-pig ileum (IC50 = 3.2 × 10-8 M). As preliminary to investigating the effect of N-3389 on 5-HT4 receptors, we examined the contraction induced by 5-HT in guinea-pig ileum preparations. We confirmed that 5-HT (10-8 - 10-5 M) induced biphasic contractions in the preparations.Furthermore, 5-HT3 receptor antagonism inhibited the late phase of the contraction induced by high concentrations of 5-HT (3 × 10-6 - 10-5 M), whereas 5-HT4 receptor antagonism inhibited the early phase of the contraction induced by low concentrations of 5-HT (10-8 - 10-6 M). N-3389 (10-7 - 10-5 M) inhibited both phases of contraction induced by 5-HT. In addition, N-3389 (3 × 10-7 -3 × 10-6 M) was found to inhibit the increase of electrically stimulated twitch responses induced by 5-HT (10-8 M) in longitudinal muscle myenteric plexus preparation of the guinea-pig ileum. These results suggest that N-3389 acts as a 5-HT3 and 5-HT4 receptor antagonist.
- 5-HT (5-hydroxytryptamine, serotonin)
- 5-HT receptor
- 5-HT receptor
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