Structural features of various proglumide-related cholecystokinin receptor antagonists.
Structural features of various proglumide-related cholecystokinin receptor antagonists.
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各种丙谷胺相关胆囊收缩素受体拮抗剂的结构特征。
DOI：
10.1152/ajpgi.1986.251.6.g839
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发表时间：
1986
期刊：
影响因子：
--
通讯作者：
J. Gardner
中科院分区：
文献类型：
--
作者：
R. Jensen;Z. Zhou;R. Murphy;S. Jones;I. Setnikar;L. Rovati;J. Gardner
研究了13种丙氨酸衍生物，它们的二烷基长度和苯甲酰取代部分不同，它们与豚鼠胰腺胆囊收缩素（CCK）受体的相互作用能力。每一种衍生物都比丙谷酰胺更有效。它们抑制cck刺激的淀粉酶释放和抑制125I-CCK结合的能力密切相关。二烷基衍生物的相对效价为正戊基大于正己基，正丁基大于正丙基。对于苯甲酰部分，加入两个吸电子基团比加入一个吸电子基团或给电子基团更能提高效能。丙烯酰胺的3,4-二氯-二正戊基衍生物的效力是丙烯酰胺的1300倍，其作用具有特异性和竞争性，在大鼠、小鼠和豚鼠胰腺中具有CCK受体拮抗剂的作用。对于所有丙氨酸衍生物，其抑制cck刺激的淀粉酶释放的能力与先前报道的抑制cck诱导的胆囊收缩的能力之间存在良好的相关性（r = 0.84, P < 0.001）。然而，某些丙氨酸衍生物对胰腺CCK受体的亲和力比介导胆囊收缩的CCK受体高得多。对于其他丙酰胺衍生物，这种模式是相反的。这些结果表明，二正烷基和取代在丙烯酰胺的苯甲酰部分是同样重要的亲和力决定因素，衍生物，如二正戊基3,4-二氯类似物，可以产生比丙烯酰胺强1300倍的效力。（摘要删节250字）
Thirteen proglumide derivatives that varied in the length of the di-n-alkyl group and in the substitutions on the benzoyl moiety were tested for their ability to interact with guinea pig pancreatic cholecystokinin (CCK) receptors. Each derivative was more potent than proglumide. There was a close correlation between their abilities to inhibit CCK-stimulated amylase release and to inhibit binding of 125I-CCK. For the di-n-alkyl derivatives the relative potency was n-pentyl greater than n-hexyl greater than n-butyl greater than n-propyl. For the benzoyl moiety, adding two electron-withdrawing groups increased potency more than adding a single electron-withdrawing group or adding electron-donating groups. The 3,4-dichloro-di-n-pentyl derivative of proglumide was 1,300 times more potent than proglumide, and its action was specific, competitive, and it functioned as a CCK receptor antagonist in rat, mouse, and guinea pig pancreas. For all proglumide derivatives there was a good correlation (r = 0.84, P less than 0.001) between their abilities to inhibit CCK-stimulated amylase release and that previously reported for their abilities to inhibit CCK-induced gallbladder contraction. However, certain proglumide derivatives had a much higher affinity for the pancreatic CCK receptor than for the CCK receptor mediating gallbladder contraction. For other proglumide derivatives the pattern was reversed. These results demonstrate that both the di-n-alkyl group and the substitution on the benzoyl moiety of proglumide are equally important determinants of affinity and that derivatives such as the di-n-pentyl 3,4-dichloro analogue can be produced that are 1,300 times more potent than proglumide.(ABSTRACT TRUNCATED AT 250 WORDS)