Al-Obeidi F, Hruby V J, Castrucci A M, Hadley M E
Department of Chemistry, University of Arizona, Tucson 85721.
J Med Chem. 1989 Jan;32(1):174-9. doi: 10.1021/jm00121a032.
alpha-Melanocyte stimulating hormone (alpha-MSH) is a linear tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) that has diverse physiological functions in addition to its reversible darkening of amphibian skins by stimulating melanosome dispersion within melanophores. On the basis of theoretical and experimental results from our laboratory and others, we have designed a group of 1-13, 4-13, and especially 4-10 analogues related to the superpotent analogue [Nle4,D-Phe7]alpha-MSH in which the Glu5 has been replaced with Asp5, and the Gly10 has been replaced with Lys10 and other basic amino acid residues in the 4-10 analogues, and in which Gly10 and Lys11 were interchanged in the longer peptide analogues. In the 1-13 and 4-13 series the Lys10, Gly11 analogues generally retained superpotency for the D-Phe7-containing analogues. Most interestingly, synthesis of Ac-[Nle4,Xxx5,Yyy7,Zzz10]alpha-MSH4-10-NH2 analogues where Xxx = Asp or Glu, Yyy = Phe or D-Phe, and Zzz = basic amino acids (Lys, Orn, alpha,gamma-diaminobutyric acid (Dab), and alpha,beta-diaminopropionic acid (Dpr] provided melanotropins with potencies up to 10 times that of the native hormone in stimulating frog (Rana pipiens) skin darkening and 8-50 times more potent than alpha-MSH in stimulating lizard (Anolis carolinensis) skin melanophores in vitro. To our knowledge, Ac-[Nle4,Asp5,D-Phe7,Dab10]alpha-MSH4-10-NH2, the most potent analogue, is the most potent melanotropin obtained thus far for the Anolis assay system. These results provide new insights into the structural and conformational requirements for biological potency of alpha-MSH and the differential structural and conformational requirements of alpha-MSH and its analogues at two different types of pigment cell receptors.
α-黑素细胞刺激素（α-MSH）是一种线性十三肽（Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2），除了通过刺激黑素细胞内的黑素体分散使两栖动物皮肤可逆性变黑外，还具有多种生理功能。根据我们实验室和其他实验室的理论和实验结果，我们设计了一组与超强效类似物[Nle4,D-Phe7]α-MSH相关的1-13、4-13，特别是4-10类似物，其中Glu5被Asp5取代，Gly10在4-10类似物中被Lys10和其他碱性氨基酸残基取代，并且在较长的肽类似物中Gly10和Lys11互换。在1-13和4-13系列中，Lys10、Gly11类似物对于含D-Phe7的类似物通常保留超强效性。最有趣的是，合成Ac-[Nle4,Xxx5,Yyy7,Zzz10]α-MSH4-10-NH2类似物，其中Xxx = Asp或Glu，Yyy = Phe或D-Phe，Zzz = 碱性氨基酸（Lys、Orn、α,γ-二氨基丁酸（Dab）和α,β-二氨基丙酸（Dpr）），所得到的促黑素在刺激青蛙（豹蛙）皮肤变黑方面的效力高达天然激素的10倍，在体外刺激蜥蜴（绿安乐蜥）皮肤黑素细胞方面比α-MSH强效8-50倍。据我们所知，Ac-[Nle4,Asp5,D-Phe7,Dab10]α-MSH4-10-NH2，即最强效的类似物，是迄今为止在绿安乐蜥测定系统中获得的最强效的促黑素。这些结果为α-MSH生物活性的结构和构象要求以及α-MSH及其类似物在两种不同类型色素细胞受体处的不同结构和构象要求提供了新的见解。
