Hagihara K, Hayakawa T, Arai T, Eguchi H, Mino S, Kawase S
Pharmaceutical Research Center, Nisshin Flour Milling Co. Ltd., Saitana, Japan.
Eur J Pharmacol. 1994 Dec 12;271(1):159-66. doi: 10.1016/0014-2999(94)90276-3.
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.
使用体外和体内试验检测了化合物N-3389（内-3,9-二甲基-3,9-二氮杂双环[3,3,1]壬-7-基1H-吲唑-3-甲酰胺二盐酸盐）对5-HT3和5-HT4受体的拮抗活性。在放射性配体结合试验中，N-3389表现出强效的5-HT3受体拮抗活性（pKi = 8.77），对大鼠2-甲基-5-羟色胺（2-Me-5-HT）诱导的心动过缓有效（静脉注射ED50 = 0.73微克/千克，口服38微克/千克），对豚鼠回肠纵肌肌间神经丛标本中2-Me-5-HT诱导的收缩有效（IC50 = 3.2×10^(-8) M）。作为研究N-3389对5-HT4受体作用的初步实验，我们检测了5-HT在豚鼠回肠标本中诱导的收缩。我们证实5-HT（10^(-8)-10^(-5) M）在标本中诱导双相收缩。此外，5-HT3受体拮抗作用抑制高浓度5-HT（3×10^(-6)-10^(-5) M）诱导的收缩后期，而5-HT4受体拮抗作用抑制低浓度5-HT（10^(-8)-10^(-6) M）诱导的收缩早期。N-3389（10^(-7)-10^(-5) M）抑制5-HT诱导的收缩两个阶段。此外，发现N-3389（3×10^(-7)-3×10^(-6) M）抑制5-HT（10^(-8) M）对豚鼠回肠纵肌肌间神经丛标本电刺激抽搐反应的增强。这些结果表明N-3389作为5-HT3和5-HT4受体拮抗剂起作用。
