EFFECT OF SEROTONIN (5-HT)(3)-RECEPTOR ANTAGONISTS YM060, YM114 (KAE-393), ONDANSETRON AND GRANISETRON ON 5-HT4 RECEPTORS AND GASTRIC-EMPTYING IN RODENTS
EFFECT OF SEROTONIN (5-HT)(3)-RECEPTOR ANTAGONISTS YM060, YM114 (KAE-393), ONDANSETRON AND GRANISETRON ON 5-HT4 RECEPTORS AND GASTRIC-EMPTYING IN RODENTS
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DOI：
10.1254/jjp.69.205
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发表时间：
1995-11-01
期刊：
影响因子：
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通讯作者：
AKUZAWA, S
中科院分区：
文献类型：
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作者：
MIYATA, K;YAMANO, M;AKUZAWA, S
我们研究了YM060 {(R)-5-[（1-甲基-3-吲哚基）羰基]-4,5,6,7-四氢- 1h -盐酸苯并咪唑}和YM114 (KAE-393) {(R)-5-[（2,3-二氢-1-吲哚基）羰基]-4,5,6,7-四氢- 1h -盐酸苯并咪唑}对正常和顺铂治疗大鼠5- ht4受体和胃排空的影响，并与ondansetron和granisetron进行了比较。YM060、YM114、ondansetron和granisetron对[H-3]GR113808{[[1-[（2-甲基磺酰基）氨基]乙基]-4-哌替啶基]甲基1-甲基- 1h -吲哚-3-羧酸盐}在豚鼠纹状体的特异性结合具有剂量依赖性，其pK(i)值分别为5.53、5.13、5.21和5.63。根据[H-3]GR65630与大鼠皮质膜5- ht3受体结合的pK(i)值，YM060、YM114、昂丹司琼和格拉司琼对5- ht4受体的亲和力分别比对5- ht3受体的亲和力低约5、5、3.5和3.5个log单位。在豚鼠肌丛纵肌和大鼠食管粘膜肌膜中，YM060和YM114对5- ht4无拮抗作用。虽然昂丹司琼在纵向肌的抽搐反应中产生了浓度依赖性的增加，但它不具有5-HT3和5- ht4的激动活性。格拉司琼拮抗5- ht诱导的大鼠食管松弛，pA(2)值为5.39。静脉注射YM060、YM114、昂丹司琼和格拉司琼显著增强大鼠胃内玻璃微珠排空，改善顺铂诱导的胃排空减缓。这些结果表明，YM060和YM114对5-HT3受体的选择性高于昂丹司琼和格拉司琼，这两种5-HT3拮抗剂在正常和顺铂治疗的大鼠中具有胃促动力学活性，而不影响5-HT4受体。
We investigated the effects of YM060 {(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydrol-1H-benzimidazole hydrochloride} and YM114 (KAE-393) {(R)-5-[(2,3-dihydro-1-indolyl)-carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride} on 5-HT4 receptors and gastric emptying in normal and cisplatin-treated rats and compared results with those for ondansetron and granisetron. YM060, YM114, ondansetron and granisetron dose-dependently inhibited the specific binding of [H-3]GR113808 {[[1-[(2-methylsulphonyl)amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1H-indole-3-carboxylate} in guinea pig striatum, with pK(i) values of 5.53, 5.13, 5.21 and 5.63, respectively. According to the pK(i) values reported in 5-HT3-receptor binding of [H-3]GR65630 to rat cortical membranes, the affinity of YM060, YM114, ondansetron and granisetron for 5-HT4 receptors was approximately 5, 5, 3.5 and 3.5 log units lower than that for 5-HT3 receptors, respectively. In the guinea pig longitudinal muscle with myenteric plexus and rat esophageal tunica muscularis mucosae, YM060 and YM114 showed neither 5-HT4-agonistic nor antagonistic properties. Although ondansetron produced concentration-dependent increases in the magnitude of the twitch response in longitudinal muscle, it did not possess 5-HT3- and 5-HT4-agonistic activity. Granisetron antagonized 5-HT-induced relaxation of the rat esophagus with an apparent pA(2) value of 5.39. Intravenous YM060, YM114, ondansetron and granisetron significantly enhanced gastric emptying of glass beads and improved cisplatin-induced slowing of gastric emptying in rats. These results indicate that the selectivity of YM060 and YM114 for 5-HT3 receptors is higher than that of ondansetron and granisetron and that these 5-HT3 antagonists have gastroprokinetic activity in normal and cisplatin-treated rats without affecting 5-HT4 receptors.