Comparative biological activities of highly potent active-site analogues of α-melanotropin

Tomi K. Sawyer, Victor J Hruby, Brian C. Wilkes, Matthew T. Draelos, Mac E. Hadley, Marvin Bergsneider

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Abstract

The heptapeptide sequence, Met-Glu-His-Phe-Arg-Trp-Gly, found in common within the primary structures of α-melanotropin (α-MSH), β-melanotropm (β-MSH), and adrenal corticotropic hormone (ACTH) may represent the active site mainly responsible for the melanotropic activities of these peptides. In α-MSH, replacement of Met by Nle at position 4 and D-Phe for its L enantiomer at position 7 produced a stereostructural analogue ([Nle4,D-Phe7]-α-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 α-MSH (α-MSH4-10). Although α-MSH4-10 has only about 1/100 000 the potency of α-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 of Met by Nle; and (3) substitution of D-Phe for L-Phe. The final peptide, Ac[Nle4,D-Phe7]-α-MSH4-10-NH2, possessed one-fifth the potency of α-MSH on the frog (Rana pipiens) skin assay and was about 10 times more potent than α-MSH in the lizard (Anolis carolinensis) assay. Ac-[Nle4,D-Phe7]-α-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]-α-MSH. Interestingly, Ac-[Tyr4]-α-MSH4-10-NH2, which was prepared to provide an analogue that might be radiolabeled, was a partial agonist in the melanoma adenylate cyclase assay. 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 heptapeptide active site of α-MSH.

Original languageEnglish (US)
Pages (from-to)1022-1027
Number of pages6
JournalJournal of Medicinal Chemistry
Volume25
Issue number9
Publication statusPublished - 1982

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Sawyer, T. K., Hruby, V. J., Wilkes, B. C., Draelos, M. T., Hadley, M. E., & Bergsneider, M. (1982). Comparative biological activities of highly potent active-site analogues of α-melanotropin. Journal of Medicinal Chemistry, 25(9), 1022-1027.