BENZODIAZEPINE ANALOGS L365,260 AND L364,718 AS GASTRIN AND PANCREATIC CCK RECEPTOR ANTAGONISTS
BENZODIAZEPINE ANALOGS L365,260 AND L364,718 AS GASTRIN AND PANCREATIC CCK RECEPTOR ANTAGONISTS
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DOI：
10.1152/ajpgi.1989.257.1.g169
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发表时间：
1989-07-01
影响因子：
--
通讯作者：
JENSEN, RT
中科院分区：
文献类型：
--
作者：
HUANG, SC;ZHANG, L;JENSEN, RT
我们研究了最近描述的3-（苯甲酰氨基）苯二氮卓类似物L365，260和3-（酰氨基）苯二氮卓类似物L364，718区分胃泌素和胰腺胆囊收缩素（CCK）受体的能力。L365，260和L364，718单独存在（1 μ M）时均不引起刺激豚鼠胰腺腺泡的淀粉酶释放或引起豚鼠胃平滑肌细胞的收缩。每个类似物抑制CCK刺激的淀粉酶释放，胃泌素-17-I刺激的平滑肌收缩，结合125 I-胃泌素-17-I的胰腺腺泡上的胃泌素受体。L365，718 a抑制125 I-胃泌素与胰腺腺泡素或胃泌素刺激的平滑肌收缩的结合。与此相反，L364，718（Ki，4 . ±.在抑制125 I-BH-CCK-8与胰腺腺泡结合或CCK刺激的淀粉酶释放方面，L365，260的效力是L365，260的145-200倍。L364，718和L365，260都不能区分高亲和力和低亲和力CCK结合位点。L365，260和L364，718不抑制放射性标记的血管活性肠肽、促胰液素、蛙皮素、P物质或N-甲基东莨菪碱与胰腺腺泡的结合。这些结果表明，与所述的其他胃泌素-CCK受体拮抗剂相比，L365，260是选择性胃泌素受体拮抗剂，其对胃泌素的亲和力比胰腺CCK受体高80倍，而L364，718对胰腺CCK受体的亲和力高125倍。由于这两种拮抗剂在CCK和胃泌素参与各种生理过程中的选择性，即使当两种受体出现在同一细胞上时，也可以区分。
We examined the ability of the recently described 3-(benzoylamino)benzodiazepine analogue L365,260 and the 3-(acylamino)benzodiazepine analogue L364,718 to distinguish gastrin from pancreatic cholecystokinin (CCK) receptors. Neither L365,260 nor L364,718 when present alone (1 .mu.M) caused stimulation of maylase release from guinea pig pancreatic acini or caused contraction of smooth muscle cells from guinea pig stomach. Each analogue inhibited CCK-stimulated amylase release, gastrin-17-I-stimulated smooth muscle contraction, binding of 125I-gastrin-17-I to gastrin receptors on pancreatic acini. L365,718 a inhibiting binding of 125I-gastrin to pancreatic acinin or gastrin--stimulated smooth muscle contraction. In contrast, L364,718 (Ki, 4 .+-. 1 nM) was 145-200 times more potent than L365,260 at inhibiting binding of 125I-BH-CCK-8 to pancreatic acini or CCK-stimulated amylase release. Neither L364,718 nor L365,260 distinguished between high- and low-affinity CCK binding sites. L365,260 and L364,718 did not inhibit binding of radiolabeled vasoactive intestinal peptide, secretin, bombesin, substance P, or N-methylscopolamine to pancreatic acini. These results demonstrate that, in contrast to other gastrin-CCK receptor antagonists described, L365,260 is a selective gastrin receptor antagonist having an 80-fold higher affinity for gastrin than pancreatic CCK receptor, whereas L364,718 has a 125-fold higher affinity for pancreatic CCK receptors. Because of the selectivity of these two antagonists in the involvement of CCK and gastrin in various physiological processes can be differentiated even when both receptors occur on the same cell.