Characterization of a new CCK antagonist, L364,718: in vitro and in vivo studies.
Characterization of a new CCK antagonist, L364,718: in vitro and in vivo studies.
复制标题
新型 CCK 拮抗剂 L364,718 的表征：体外和体内研究。
DOI：
10.1152/ajpgi.1988.255.3.g261
复制
发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Owyang,C
中科院分区：
文献类型：
--
作者：
Louie,DS;Liang,JP;Owyang,C
在本研究中，我们研究了一种新型口服有效的非肽缩胆囊素 (CCK) 拮抗剂 3S(-)-N-(2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯二氮卓-3-基)-1H-吲哚-2-甲酰胺 (L364,718) 对 CCK 诱导的淀粉酶释放的影响。我们使用分离的大鼠胰腺腺泡并将其与 CCK-8（有或没有各种 CCK 受体拮抗剂）一起孵育。 L364,718 (3-100 nM)、丙谷胺 (1-10 mM) 和丙谷胺衍生物 CR1409 (1-30 microM) 各自引起 CCK-8 剂量反应曲线进行性右移，但最大淀粉酶分泌没有变化。根据Schild的方法绘制数据表明竞争性抑制。 L364、718、CR1409 和丙谷胺的 Kis 分别为 0.25 nM、0.15 microM 和 0.5 mM。因此，在抑制CCK-8诱导的淀粉酶释放方面，L364,718比CR1409更有效600倍，比丙谷胺更有效2,000,000倍。这些受体拮抗剂对 125I-Bolton-Hunter-CCK-8 与腺泡结合的抑制具有相似的等级效力。 L364,718 针对其他胰腺外分泌促分泌剂进行了测试，并且对仅通过 CCK 受体起作用的激动剂有效。在大鼠中，胰液从十二指肠转移会刺激胰淀粉酶输出并升高血浆 CCK 水平。静脉内施用L364,718可阻断受刺激的淀粉酶分泌。此外，通过从十二指肠转移胰液，从大鼠中提取血浆CCK，刺激胰腺腺泡释放淀粉酶，并且通过添加L364,718来阻断这种刺激。（摘要截断为250字）
In this study we examined a novel, orally effective, nonpeptidal cholecystokinin (CCK) antagonist, 3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl) -1H-indole-2-carboxamide (L364,718) on CCK-induced amylase release. We used isolated rat pancreatic acini and incubated them with CCK-8 with or without various CCK receptor antagonists. L364,718 (3-100 nM), proglumide (1-10 mM), and the proglumide derivative CR1409 (1-30 microM) each caused a progressive rightward shift in the CCK-8 dose-response curve without a change in maximal amylase secretion. Plotting the data according to the method of Schild indicated competitive inhibition. The Kis for L364,718, CR1409, and proglumide were 0.25 nM, 0.15 microM, and 0.5 mM, respectively. Thus L364,718 was 600-fold more potent than CR1409 and 2,000,000-fold more potent than proglumide in inhibiting CCK-8-induced amylase release. Inhibition of 125I-Bolton-Hunter-CCK-8 binding to acini by these receptor antagonists had a similar rank potency. L364,718 was tested against other pancreatic exocrine secretagogues and was effective against agonists that only act through the CCK receptor. In rats, diversion of pancreatic juice from the duodenum stimulated pancreatic amylase output and elevated plasma CCK levels. The stimulated amylase secretion was blocked by intravenous administration of L364,718. Furthermore, extracted plasma CCK from rats with diversion of pancreatic juice from the duodenum stimulated amylase release from pancreatic acini, and this stimulation was blocked by addition of L364,718.(ABSTRACT TRUNCATED AT 250 WORDS)