Differentiation of the structural features of melanotropins important for biological potency and prolonged activity in vitro


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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 of l‐Phe in position 7 by d‐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 potency in vitro. Particularly noteworthy is the observation that the 4–11 fragment analogue Ac‐[Nle4]‐α‐MSH4–11‐NH2 is 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) following removal of exogenous peptide from the bioassay medium showed striking differences in the two systems. On the lizard skin assay, only [Nle4, d‐Phe7]‐α‐MSH, Ac‐[Nle4, d‐Phe7]‐α‐MSH4–11‐NH2 and Ac‐[Nle4, d‐Phe7]‐α‐MSH4–10‐NH2 effect 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‐NH2 exhibited 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.

Original languageEnglish (US)
Pages (from-to)313-324
Number of pages12
JournalInternational journal of peptide and protein research
Issue number3
StatePublished - Sep 1983


  • melanocyte stimulating hormone (MSH)
  • melanophores
  • melanotropin structure‐activity

ASJC Scopus subject areas

  • Biochemistry


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