Design of Potent Linear ±-Melanotropin 4–10 Analogues Modified in Positions 5 and 10

Fahad Al-Obeidi, Victor J. Hruby, Ana M. De L Castrucci, Mac E. Hadley

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

a-Melanocyte stimulating hormone (a-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] α-MSH in which the Glu5has 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 Gly10and Lys11were 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]a-MSH4_10-NH2 analogues where Xxx = Asp or Glu, Yyy = Phe or D-Phe, and Zzz = basic amino acids (Lys, Orn, α,γ-diaminobutyric acid (Dab), and α,β-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 a-MSH in stimulating lizard (Anolis carolinensis) skin melanophores in vitro. To our knowledge, Ac- [Nle4,Asp5,D-Phe7,Dab10] α-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 a-MSH and the differential structural and conformational requirements of a-MSH and its analogues at two different types of pigment cell receptors.

Original languageEnglish (US)
Pages (from-to)174-179
Number of pages6
JournalJournal of Medicinal Chemistry
Volume32
Issue number1
DOIs
StatePublished - Jan 1 1989

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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