Biological activities of cyclic enkephalin pseudopeptides containing thioamides as amide bond replacements.
Biological activities of cyclic enkephalin pseudopeptides containing thioamides as amide bond replacements.
复制标题
含有硫代酰胺作为酰胺键替代物的环状脑啡肽伪肽的生物活性。
DOI：
10.1016/0006-291x(89)90790-0
复制
发表时间：
1989
影响因子：
3.1
通讯作者：
Schiller,PW
中科院分区：
文献类型：
--
作者：
Sherman,DB;Spatola,AF;Wire,WS;Burks,TF;Nguyen,TM;Schiller,PW
制备了h - tyr - cycloo （nε - d - lys - gly - ph - leu）类似物，其在3-4位（单硫代）、3-4和5-2位（双硫代）和2-3、3-4和5-2位（三硫代）含有硫酰胺。这些化合物已经在μ-和δ-受体选择性生物和结合实验中测试了阿片活性。随着硫含量的增加，其在豚鼠回肠中的生物活性下降，在小鼠输精管实验中的生物活性略有波动。令人惊讶的是，化合物的δ选择性随着硫的增加而增加。在结合实验中，硫酰胺类似物倾向于保持对μ受体的亲和力。单硫代和二硫代类似物的μ选择性高于亲本，而三硫代类似物的δ选择性高于亲本。这些结果表明，硫与氧的微妙交换可能对受体的选择性和亲和力产生重大影响，并可能反映了结合与生物转导事件的不同构象/结构要求。
Analogs of H-Tyr-cyclo(Nε-D-Lys-Gly-Phe-Leu) have been prepared which contain thioamides at the 3–4 position (monothio), 3–4 and 5-2 positions (dithio), and 2–3, 3–4, and 5-2 positions (trithio). These compounds have been tested for opioid activity in μ- and δ-receptor selective bio- and binding assays. As the number of sulfurs increased, the biological activities dropped on the guinea pig ileum and fluctuated modestly on the mouse vas deferens assay. Surprisingly, the compounds displayed increasing δ selectivity as the number of sulfurs increased. In the binding assay, the thioamide analogs tended to retain affinity toward the μ receptor. The mono- and dithio-analogs were more μ selective than the parent, while the trithio-analog was more δ selective. These results suggest that the subtle exchange of sulfur for oxygen can have a significant impact on receptor selectivity and affinity, and probably reflect the different conformational/structural requirements for binding vs. the biological transduction event.