Antagonistic activities of N-3389, a newly synthesized diazabicyclo derivative, at 5-HT3 and 5-HT4 receptors.

The antagonistic activities of compound N-3389 (endo-3,9-dimethyl-3,9- diazabicyclo[3,3,1]non-7-yl 1H-indazole-3-carboxamide dihydrochloride) 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 micrograms/kg i.v., 38 micrograms/kg p.o.) and against 2-Me-5-HT-induced contraction in longitudinal muscle myenteric plexus preparations of guinea-pig ileum (IC50 = 3.2 x 10(-8) M). As a 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 x 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 x 10(-7)-3 x 10(-6) M) was found to inhibit the increase of electrically stimulated twitch responses induced by 5-HT (10(-8) M) 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.