New proglumide-analogue CCK receptor antagonists: very potent and selective for peripheral tissues.
New proglumide-analogue CCK receptor antagonists: very potent and selective for peripheral tissues.
复制标题
新型丙谷胺类似物 CCK 受体拮抗剂：对于外周组织非常有效且具有选择性。
DOI：
10.1152/ajpgi.1986.250.6.g856
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发表时间：
1986
期刊：
影响因子：
--
通讯作者：
Grendell,JH
中科院分区：
文献类型：
--
作者：
Niederau,C;Niederau,M;Williams,JA;Grendell,JH
本研究评估了最近合成的两个丙谷胺类似物，均为4-苯甲酰胺-N，N-二烷基-戊二胺酸衍生物，作为CCK受体拮抗剂的能力。这两种新的拮抗剂都能抑制由CCK刺激的淀粉酶的释放，也同样能抑制~(125)I-CCK与大鼠胰腺腺泡的结合。这些效应表现出竞争性动力学；两种拮抗剂都没有表现出激动剂活性，而且都是特异的，因为只有那些与CCK受体相互作用的促分泌剂被抑制。这两种拮抗剂也抑制125I-CCK与小鼠胰腺膜颗粒的结合，其结果与大鼠胰腺腺泡相似。随着两个新拮抗剂的作用增强，在低浓度(约10(-7)M)时，对CCK的作用和结合的抑制达到半极大；与丙谷胺相比，新拮抗剂的作用强达4000倍。与丙谷胺不同的是，丙谷胺以类似的方式抑制胆囊收缩素与胰腺和脑组织的结合，与大脑相比，这两种拮抗剂在低得多的浓度下抑制胆囊收缩素与胰腺的结合。与大脑相比，越强的抑制剂在抑制胆囊收缩素与胰腺组织结合方面的效力是大脑的300倍。
The present study evaluates the ability of two recently synthesized analogues of proglumide, both 4-benzamido-N,N-di-alkyl-glutaramic acid derivatives, to act as cholecystokinin receptor antagonists. Both new antagonists inhibited cholecystokinin-stimulated amylase release and, similarly, binding of 125I-cholecystokinin to isolated rat pancreatic acini. These effects displayed competitive kinetics; both antagonists showed no agonist activity and were specific in that only those secretagogues were inhibited that interact with the cholecystokinin receptor. Both antagonists also inhibited binding of 125I-cholecystokinin to mouse pancreatic membrane particles similarly to results with rat pancreatic acini. With the more potent of the two new antagonists, half-maximal inhibition of action and binding of cholecystokinin was observed with low concentrations of approximately 10(-7) M; compared with proglumide, the new antagonists were as much as 4,000 times more potent. Unlike proglumide, which inhibits binding of cholecystokinin to pancreas and brain tissue similarly, both antagonists inhibited binding of cholecystokinin to the pancreas at much lower concentrations compared with brain. The more potent of the inhibitors was 300 times more potent in inhibiting binding of cholecystokinin to pancreatic tissues compared with brain.