Deltorphin analogs restricted via a urea bridge: structure and opioid activity.
Deltorphin analogs restricted via a urea bridge: structure and opioid activity.
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通过尿素桥限制的德尔托芬类似物：结构和阿片类药物活性。
DOI：
10.1002/psc.1010
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
Izdebski,Jan
中科院分区：
文献类型：
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作者：
Zieleniak,Agnieszka;Rodziewicz-Motowidło,Sylwia;Rusak,Lukasz;Chung,NgaN;Czaplewski,Cezary;Witkowska,Ewa;Schiller,PeterW;Ciarkowski,Jerzy;Izdebski,Jan
合成了与deltorphin全序列相关的8个环七肽。在4‐甲基苯基苯胺树脂上合成了含有2位和4位二氨基残基的线性肽。根据保护程序的不同，可以得到具有N保护的肽树脂或侧链上有游离氨基的N保护肽酰胺，随后用双（4 -硝基苯基）碳酸酯处理以形成尿素单元。在豚鼠回肠（GPI）和小鼠输精管（MVD）实验中测定了这些肽的阿片活性。一些化合物表现出高的δ阿片受体激动剂效力和δ受体的高选择性。将结果与之前分别得到的1-4个三角海豚类似物进行了比较。这些肽的构象已经用二维核磁共振在H2O/D2O和分子动力学中进行了研究。我们观察到主环具有明确的构象，而Tyr和Phe侧链以及c末端尾部具有明显的构象自由度。将这些多肽的生物测定数据和构象参数与先前描述的相应的1-4三角海豚类似物进行比较。这种比较允许评估c末端肽段在定义theN末端部分的构象和受体相互作用中的作用，并提供了对假定的生物活性构象和生物活性之间关系的见解。版权所有©2008欧洲多肽协会和约翰威利父子有限公司
Eight cyclic heptapeptides related to the full sequence of deltorphin have been synthesized. The synthesis of linear peptides containing diamino acid residues in positions 2 and 4 was carried out on a 4‐methylbenzhydrylamine resin. Depending on protection procedures, the N‐protected peptide‐resins or N‐protected peptide amides with free amino groups in the side chains were obtained, which were subsequently treated with bis‐(4‐nitrophenyl)carbonate to form a urea unit. Opioid activities of the peptides were determined in the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays. Several compounds showed high δ opioid agonist potency and high selectivity for δ receptors. The results were compared with those obtained earlier for respective 1–4 deltorphin analogs. The conformations of these peptides have been studied using 2D‐NMR in H2O/D2O and molecular dynamics. We observed that the backbone rings had well defined conformations, while the Tyr and Phe side chains and theC‐terminal tail had significant conformational freedom. The bioassay data and conformational parameters of these peptides were compared with those of previously described, corresponding 1–4 deltorphin analogs. This comparison permitted an assessment of the role of theC‐terminal peptide segment in defining the conformation and receptor interaction of theN‐terminal portion and provided insight into the relationship between the putative bioactive conformations and bioactivity. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.