Comparative biological activities of highly potent active-site analogues of alpha-melanotropin.
Comparative biological activities of highly potent active-site analogues of alpha-melanotropin.
复制标题
α-促黑素激素高效活性位点类似物的生物活性比较。
DOI：
10.1021/jm00351a004
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发表时间：
1982
影响因子：
7.3
通讯作者：
Bergsneider,M
中科院分区：
文献类型：
--
作者：
Sawyer,TK;Hruby,VJ;Wilkes,BC;Draelos,MT;Hadley,ME;Bergsneider,M
七肽序列Met-Glu-His-Phe-Arg-Trp-Gly在α-促黑素(-MSH)、β-促黑激素(？-MSH)和肾上腺促肾上腺皮质激素(ACTH)的一级结构中都存在，可能代表了这些多肽的活性部位。在-MSH中，第4位用Nle取代蛋氨酸，第7位用D-Phe取代其L对映体，得到了一个具有超强激动剂效力和超长生物活性的立体结构类似物([Nle4，o-Phe7]-a-MSH)。我们已经确定了这些化学修饰对七肽建议的活性部位-MSH(a-MSH4_10)的促黑活性的影响程度。尽管α-MSH_4_10在蛙皮试验中的效力仅为-MSH，但通过(1)N-端和C-端残基的乙酰化和酰胺化，(2)用Nle取代Met，以及(3)用D-Phe取代L-Phe，都能增强α-MsH的促黑活性。最终的多肽Ac-[Nle4，D-Phe7]-a-MSH4_10-NH2在蛙类皮肤试验中的效力是-MSH的五分之一，在蜥蜴(Anolis Carolinens)的试验中效力约为-MSH的10倍。AC-[Nle4，D-Phe7]-a-MSH410-NH2在刺激小鼠黑色素瘤腺苷环化酶方面的活性也是天然激素的8倍左右。这种立体结构的七肽类似物在Anolis皮肤试验中相对于MSH显著延长了促黑作用，但在蛙皮试验中相对于十三肽类似物[Nle4，D-Phe7]-MSH延长的时间较短。有趣的是，Ac-[Tyr4]-a-MSH4_10-NH2是黑色素瘤腺苷循环分析中的部分激动剂，它被准备提供一种可能被放射性标记的类似物。此外，尽管该化合物在所有检测中都表现出很低的效价，但在青蛙皮肤检测中表现出异常长时间的促黑素活性。这些结果表明，由Nle4取代Met4和由D-Phe取代Phe7而导致的天然激素效力和活性的显著变化主要(但不完全是)源于a-MSH七肽活性部位的这些变化。
The heptapeptide sequence, Met-Glu-His-Phe-Arg-Trp-Gly, found in common within the primary structures of a-melanotropin (-MSH), ß-melanotropin (ß-MSH), and adrenal corticotropic hormone (ACTH) may represent the active site mainly responsible for the melanotropic activities of these peptides. In-MSH, replacement of Met by Nle at position 4 and D-Phe for its L enantiomer at position 7 produced a stereostructural analogue ([Nle4, o-Phe7]-a-MSH) with superagonist potency and extraordinarily prolonged biological activity. We have determined the extent to which these chemical modifications affect the melanotropic activity of the heptapeptide-proposed active site of-MSH (a-MSH4_10). Although a-MSH4_10 has only about Viooooo the potency of-MSH in the frog skin assay, melanotropic activity was enhanced by (1) acetylation and amidation of the N-and C-terminal residues, respectively;(2) replacement ofMet byNle; and (3) substitution of D-Phe for L-Phe. The final peptide, Ac-[Nle4, D-Phe7]-a-MSH4_10-NH2, possessed one-fifth the potency of-MSH on the frog (Rana pipiens) skin assay and was about 10 times more potent than-MSH inthe lizard (Anolis carolinensis) assay. Ac-[Nle4, D-Phe7]-a-MSH4_10-NH2 was also about 8 times more active than the native hormone in stimulating mouse melanoma adenylate cyclase. The melanotropic activity of this stereostructural heptapeptide analogue was dramatically prolonged relative to MSH in the Anolis skin assay but was less prolonged in the frog skin assay relative to the tridecapeptide analogue,[Nle4, D-Phe7]--MSH. Interestingly, Ac-[Tyr4]-a-MSH4_10-NH2, which was prepared to provide an analogue that might be radiolabeled, was a partial agonist in the melanoma adenylate cyclaseassay. Moreover, although this compound exhibited very low potency in all assays, it exhibited exceptionally prolonged melanotropic activity in the frog skin assay. These results demonstrate that the dramatic changes in potency and prolongation of activity of the native hormone which result from substitution of Met4 by Nle4 and Phe7 by D-Phe are derived primarily, but not exclusively, from these changes within the heptapeptideactive site of a-MSH.