Weng J H, Bado A, Garbay C, Roques B P
Département de Pharmacochimie Moléculaire et Structurale U266 INSERM -URA D 1500 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Faculté de Pharmacie, Paris, France.
Regul Pept. 1996 Aug 27;65(1):3-9. doi: 10.1016/0167-0115(96)00065-1.
Recently, we proposed a CCK-B agonist bioactive conformation characterized by an 'S' shape of the peptidic backbone which was derived from structure-activity relationships and conformational analysis of CCK4 (Trp-Met-Asp-Phe-NH2) analogues. Using this template, we report here the synthesis of cyclic CCK4 analogues which contain, in place of the Trp-Met dipeptide, a diketopiperazine moiety resulting from a cyclization between Nle and N-substituted (D)Trp residues and coupled with a small linker to Asp-Phe-NH2. Some of these compounds displayed good affinities and selectivities for the CCK-B receptor. The results are discussed in terms of size, hydrophobicity and spatial orientation of the side-chains on the diketopiperazine ring. The most potent ligand exhibited potent and full CCK-B receptor agonist properties in promoting the hydrolysis of inositol phosphates (EC50 = 8 nM) in CHO cells, stably transfected with the rat brain CCK-B receptor. This compound was also shown to be a potent selective CCK-B/gastrin receptor agonist since, it increased gastric acid secretion measured in anesthetized rats on i.v. administration. These compounds provide a rigid template for the design of non-peptide CCK-B agonists, by modification of the remaining peptide moiety.
最近，我们提出了一种CCK-B激动剂生物活性构象，其特征为肽主链呈“S”形，这是通过对CCK4（色氨酸-甲硫氨酸-天冬氨酸-苯丙氨酸-NH2）类似物的构效关系和构象分析得出的。利用该模板，我们在此报告环状CCK4类似物的合成，其中用Nle与N-取代（D）色氨酸残基之间环化产生的二酮哌嗪部分取代色氨酸-甲硫氨酸二肽，并通过一个小连接子与天冬氨酸-苯丙氨酸-NH2偶联。这些化合物中的一些对CCK-B受体表现出良好的亲和力和选择性。从二酮哌嗪环上侧链的大小、疏水性和空间取向方面对结果进行了讨论。最有效的配体在稳定转染大鼠脑CCK-B受体的CHO细胞中，在促进肌醇磷酸水解（EC50 = 8 nM）方面表现出强效且完全的CCK-B受体激动剂特性。该化合物还被证明是一种强效选择性CCK-B/胃泌素受体激动剂，因为在静脉注射时，它增加了麻醉大鼠胃酸分泌的测量值。通过修饰剩余的肽部分，这些化合物为非肽CCK-B激动剂的设计提供了一个刚性模板。
