Differentiation of the structural features of melanotropins important for biological potency and prolonged activity in vitro.
Differentiation of the structural features of melanotropins important for biological potency and prolonged activity in vitro.
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促黑激素结构特征的分化对于生物效力和体外延长活性很重要。
DOI：
10.1111/j.1399-3011.1983.tb02097.x
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
Hadley,ME
中科院分区：
文献类型：
--
作者：
Wilkes,BC;Sawyer,TK;Hruby,VJ;Hadley,ME
已经合成了几种α-促黑素激素（α-MSH）类似物，并测试了它们的促黑素激素活性，以确定α-MSH主要活性序列附近的某些氨基酸H-（Glu）-His-Phe-Arg-Trp-Gly-OH对激素生物活性的功能重要性。特别是，我们已经检查了4和11位与7位的l-Phe被d-Phe取代对激素的效力和延长活性的重要性。在青蛙（蛙）皮肤系统的相对效力为：[Nle4，d-Phe7]-α-MSH（60）> α-MSH（1.0）> Ac-[Nle4，d-Phe7]-α-MSH4-11-NH2（0.16）> Ac-[Nle4，d-Phe7]-α-MSH4-10-NH2（0.02）· Ac-[d-Phe7]-α-MSH5-11-NH2（0.01）> Ac-[Nle4]-α-MSH4-10-NH2（0.002）= Ac-[Nle4]-α-MSH4-11-NH2> Ac-α-MSH4-10-NH2（0.0003）· Ac-α-MSH5-11-NH2（0.0002）。另一方面，蜥蜴的相对效力（Anolis carolinensis）皮肤系统被发现是：AC-[Nle 4，d-Phe 7]-α-MSH4-10-NH2（10）· AC-[Nle 4，d-Phe 7]-α-MSH4-11-NH2（8.0）· Ac-[Nle4，d-苯丙氨酸7]-α-MSH（5.0）> α-MSH（1.0）= Ac-[Nle4]-α-MSH4-11-NH2= Ac-[d-Phe7]-α-MSH5-11-NH2> Ac-[Nle4]-α-MSH4-10-NH2（0.06）> Ac-α-MSH5-11-NH2（0.01）> Ac-α-MSH4-10-NH2（0.004）。对这些数据的详细分析表明，4、7和11位残基的立体结构关系在体外促黑素活性方面存在物种依赖性差异。特别值得注意的是，在蜥蜴试验系统中观察到4-11片段类似物Ac-[Nle 4]-α-MSH 4 -11-NH 2与α-MSH等效，这表明1-3、12、α-促黑素类似物在两种体系中的作用存在显著差异。在蜥蜴皮肤试验中，与α-MSH相比，只有[Nle 4，d-Phe 7]-α-MSH、Ac-[Nle 4，d-Phe 7]-α-MSH 4 -11-NH 2和Ac-[Nle 4，d-Phe 7]-α-MSH 4 -10-NH 2效应显示出延长的促黑素活性。相比之下，在蛙皮试验中，仅[Nle 4，d-Phe 7]-α-MSH、Ac-[Nle 4，d-Phe 7]-α-MSH 4 -11-NH 2、Ac-α-MSH 5 -11-NH 2和Ac-[Nle 4]-α-MSH 4 -10-NH 2表现出显著的延长活性。这些结果表明，相对效价和促黑素活性的延长不直接相关，而是与结合和信号转导相关的肽-受体相互作用的不同种属依赖性结构和地形要求的表现。
Several α‐melanotropin (α‐MSH) analogues have been synthesized and tested for their melanotropin activities in order to determine the functional importance of certain amino acids near the primary active sequence of α‐MSH, H‐(Glu)‐His‐Phe‐Arg‐Trp‐Gly‐OH, on the biological activities of the hormone. In particular, we have examined the importance of the 4 and 11 positions in conjunction with the substitution ofl‐Phe in position 7 byd‐Phe on potency and prolonged activity of the hormone. In the frog (Rana pipiens) skin system the relative potencies were found to be: [Nle4,d‐Phe7]‐α‐MSH (60) > α‐MSH (1.0) > Ac‐[Nle4,d‐Phe7]‐α‐MSH4–11‐NH2(0.16) > Ac‐[Nle4,d‐Phe7]‐α‐MSH4–10‐NH2(0.02) · Ac‐[d‐Phe7]‐α‐MSH5–11‐NH2(0.01) > Ac‐[Nle4]‐α‐MSH4–10‐NH2(0.002) = Ac‐[Nle4]‐α‐MSH4–11‐NH2> Ac‐α‐MSH4–10‐NH2(0.0003) · Ac‐α‐MSH5–11‐NH2(0.0002). On the other hand the relative potencies on the lizard (Anolis carolinensis) skin system were found to be: Ac‐[Nle4,d‐Phe7]‐α‐MSH4–10‐NH2(10) · Ac‐[Nle4,d‐Phe7]‐α‐MSH4–11‐NH2(8.0) · Ac‐[Nle4,d‐Phe7]‐α‐MSH (5.0) > α‐MSH (1.0) = Ac‐[Nle4]‐α‐MSH4–11‐NH2= Ac‐[d‐Phe7]‐α‐MSH5–11‐NH2> Ac‐[Nle4]‐α‐MSH4–10‐NH2(0.06) > Ac‐α‐MSH5–11‐NH2(0.01) > Ac‐α‐MSH4–10‐NH2(0.004). Detailed analyses of these data suggest species‐dependent differences in the stereostructural relationships of the residues in the 4, 7, and 11 positions for melanotropic potencyin vitro.Particularly noteworthy is the observation that the 4–11 fragment analogue Ac‐[Nle4]‐α‐MSH4–11‐NH2is equipotent to α‐MSH in the lizard assay system, suggesting that the 1–3, 12, and 13 residues of α‐MSH are not involved in the binding or transduction in this system.Examination of the ability of these α‐melanotropin analogues to effect sustained biological activity (prolongation) followingremoval of exogenous peptide from the bioassay mediumshowed striking differences in the two systems. On the lizard skin assay, only [Nle4,d‐Phe7]‐α‐MSH, Ac‐[Nle4,d‐Phe7]‐α‐MSH4–11‐NH2and Ac‐[Nle4,d‐Phe7]‐α‐MSH4–10‐NH2effect marked prolonged melanotropic activity as compared to α‐MSH. In contrast, on the frog skin assay, only [Nle4,d‐Phe7]‐α‐MSH, Ac‐[Nle4,d‐Phe7]‐α‐MSH4–11‐NH2, Ac‐α‐MSH5–11‐NH2, and Ac‐[Nle4]‐α‐MSH4–10‐NH2exhibited significant prolonged activity. These results demonstrate that relative potency and prolongation of melanotropic activity are not directly related, but rather are the manifestation of different, species‐dependent structural and topographical requirements for peptide‐receptor interactions related to binding and signal transduction.