Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of γ-MSH analogs substituted with L-alanine

P. Grieco, P. Balse-Srinivasan, G. Han, V. J. Hruby*, D. Weinberg, T. MacNeil, L. H.T. Van Der Ploeg

*Corresponding author for this work

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32 Citations (Scopus)


To elucidate the molecular basis of the interaction of the native dodecapeptide γ-MSH with the melanocortin receptors, we performed a structure-activity study in which we systematically replaced L-Ala in each position of this peptide. Here we report the binding affinity and agonist potency on human MC3R, MC4R and MC5R. Intracellular cAMP concentration was measured on CHO cells, and binding assays were carried out using membranes prepared from these cell lines which stably express hMC3R, hMC4R and hMC5R. Our results indicate that the last four amino acids in the C-terminal region of γ-MSH are not important determinants of biological activity and selectivity at human melanocortin receptors. Interesting results were obtained when L-Ala was substituted for His6, Phe7, Arg8 and Trp9. For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in γ-MSH is important for activity at these three melanocortin receptors. Similar results were obtained when Met3 was replaced with L-Ala, suggesting the importance of this position in the interaction with all three receptors. This study highlights the role played by the His-Phe-Arg-Trp sequence in receptor binding and in agonist activity of γ-MSH.

Original languageEnglish
Pages (from-to)203-210
Number of pages8
JournalJournal of Peptide Research
Issue number5
Publication statusPublished - 2002
Externally publishedYes


  • Cyclic AMP
  • Human melanocortin receptors
  • Receptor binding
  • Structure-activity
  • γ-MSH

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