Investigation of peripheral cholecystokinin receptor heterogeneity by cyclic and related linear analogues of CCK26-33: synthesis and biological properties.
Investigation of peripheral cholecystokinin receptor heterogeneity by cyclic and related linear analogues of CCK26-33: synthesis and biological properties.
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DOI：
10.1021/jm00389a002
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发表时间：
1987-06
影响因子：
7.3
通讯作者：
B. Charpentier;C. Durieux;I. Menant;B. Roques
中科院分区：
文献类型：
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作者：
B. Charpentier;C. Durieux;I. Menant;B. Roques
通过用Boc[Nle 28，31] CCK 27 -33（一种与CCK 8具有相同活性的衍生物）中的D-Lys残基替换柔性Gly 29残基（据报告，该残基在CCK 8折叠中起关键作用），研究了CCK 26 -33 [Asp-Tyr（SO 3 H）-Met-Gly-Trp-Met-Asp-Phe-NH 2]（CCK 8）外周受体的可能异质性。线性肽Boc-Asp-Tyr（SO 3 H）-Nle-D-Lys-Trp-Nle-Asp-Phe-NH 2通过Asp 26和D-Lys 29侧链之间的酰胺键形成而环化，得到肽Boc-Asp-Tyr（SO 3 H）-Nle-D-Lys-Trp-Nle-Asp-Phe-NH 2。类似物1和2显示出刺激大鼠胰腺分泌淀粉酶，其效力分别比CCK 8低40和80倍。相反，这两种肽对CCK 8诱导的豚鼠回肠收缩起弱拮抗剂作用（EC 50约为10（-5）M）。通过从1和2中去除苯丙氨酸获得的肽3和4在所有生物测定中均无活性，尽管它们的C-末端Asp 32残基被酰胺化，这是已知在CCK 7中诱导拮抗剂性质的修饰。在Boc[Asp 28，Lys 31] CCK 27 -33中残基28和31之间的环化得到化合物Boc-Tyr（SO 3 H）-Asp-Gly-Trp-Lys-Asp-Phe-NH 2，其在所有生物测定中均无活性。这些首次描述的CCK 8的环状类似物的药理学性质与其对脑和胰腺受体的结合亲和力一致，表明外周受体的异质性的存在，并强调环肽在结构-活性研究中的有用性。
A possible heterogeneity of peripheral receptors for CCK26-33 [Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] (CCK8) was investigated by replacement of the flexible Gly29 residue, reported to be crucially involved in the CCK8 folding, by a D-Lys residue in Boc[Nle28,31]CCK27-33, a derivative as active as CCK8. The linear peptide Boc-Asp-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 was cyclized through amide bond formation between the side chains of Asp26 and D-Lys29 to give the peptide Boc-Asp-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2. Analogues 1 and 2 were shown to stimulate secretion of amylase from rat pancreas with a potency that was respectively 40 and 80 times lower than that of CCK8. In contrast, both peptides acted as weak antagonists (EC50 approximately 10(-5) M) of the CCK8-induced contractions of guinea pig ileum. Peptides 3 and 4 obtained by removal of the phenylalanine from 1 and 2 were inactive in all bioassays despite amidification of their C-terminal Asp32 residue, a modification known to induce antagonist properties in CCK7. Cyclization between residues 28 and 31 in Boc[Asp28,Lys31]CCK27-33 gave compound Boc-Tyr(SO3H)-Asp-Gly-Trp-Lys-Asp-Phe-NH2, which was inactive in all bioassays. The pharmacological properties of these first described cyclic analogues of CCK8 were in agreement with their binding affinity to brain and pancreas receptors, suggesting the existence of a heterogeneity of peripheral receptors and emphasizing the usefulness of cyclic peptides in structure-activity studies.