胆囊收缩素类肽配体中受体选择性和功能活性的修饰。

Modification of receptor selectivity and functional activity in cholecystokinin peptoid ligands.

作者信息

Dezube M, Sugg E E, Birkemo L S, Croom D K, Dougherty R W, Ervin G N, Grizzle M K, James M K, Johnson M F, Mosher J T

机构信息

Department of Medicinal Chemistry, Glaxo Research Institute, Research Triangle Park, North Carolina 27709, USA.

出版信息

J Med Chem. 1995 Aug 18;38(17):3384-90. doi: 10.1021/jm00017a022.

DOI:10.1021/jm00017a022

PMID:7650691

Abstract

Hybrid analogs of the cholecystokinin A (CCK-A) receptor selective tetrapeptide agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (1,A-71623) and the CCK-B receptor selective antagonists PD-135118 (2) and CI-988 (3) were prepared. Incorporation of the Lys(Tac) side chain into 2 produced a moderately potent antagonist of CCK-8 in the isolated guinea pig gallbladder (GPGB). Incorporation of the Lys(Tac) side chain into 3 produced the novel agonist analog 7 (EC50 = 28 nM in the GPGB) with excellent affinity for both human CCK-A (IC50 = 12 nM) and CCK-B (IC50 = 17 nM) receptors. Analog 7 was a full agonist (EC50 = 3.5 nM) for calcium mobilization on CHO-K1 cells expressing hCCK-A receptors but a partial agonist on CHO-K1 cells expressing hCCK-B receptors, eliciting a weak agonist response (EC50 = 2800 nM) and antagonizing CCK-8-induced calcium mobilization (KB = 20 nM). Despite this unusual in vitro profile, analog 7 was a potent anorectic agent in rats (ED50 = 30 nmol/kg) following intraperitoneal administration.

摘要

制备了胆囊收缩素A（CCK-A）受体选择性四肽激动剂Boc-Trp-Lys（Tac）-Asp-MePhe-NH2（1，A-71623）与CCK-B受体选择性拮抗剂PD-135118（2）和CI-988（3）的杂合类似物。将Lys（Tac）侧链引入2中，在分离的豚鼠胆囊（GPGB）中产生了一种中等效力的CCK-8拮抗剂。将Lys（Tac）侧链引入3中产生了新型激动剂类似物7（在GPGB中EC50 = 28 nM），对人CCK-A（IC50 = 12 nM）和CCK-B（IC50 = 17 nM）受体均具有优异的亲和力。类似物7对于在表达hCCK-A受体的CHO-K1细胞上的钙动员是完全激动剂（EC50 = 3.5 nM），但在表达hCCK-B受体的CHO-K1细胞上是部分激动剂，引发弱激动剂反应（EC50 = 2800 nM）并拮抗CCK-8诱导的钙动员（KB = 20 nM）。尽管具有这种不寻常的体外特征，但类似物7在腹腔注射后在大鼠中是一种有效的食欲抑制剂（ED50 = 30 nmol/kg）。