Design and synthesis of highly potent and selective melanotropin analogues of SHU9119 modified at position 6

Paolo Grieco, Guoxia Han, Victor J. Hruby, David Weinberg, L. H.T. Van der Ploeg

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The melanocortin receptors are involved in several important physiological functions. The potent and enzymatically stable analogues MT-II (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2) and SHU9119 (Ac-Nle-c[Asp-His-DNal(2′)-Arg-Trp-Lys]-NH2) are important ligands of these receptors but are relatively nonselective. To differentiate between the physiological functions of these receptors, agonists, and antagonists with improved receptor selectivities are needed. We report here analogues of the well-characterized antagonist SHU9119 in which we replaced His6 with conformationally constrained amino acids. By this structure-activity study we discovered two important compounds, PG-901 (Ac-Nle4-c[Asp5-Pro6-DNal(2′) 7-Arg8-Trp9-Lys10]-NH 2) and PG-911 (Ac-Nle4-c[Asp5-Hyp6-DNal(2′) 7-Arg8-Trp9-Lys10]-NH 2), characterized to be full agonists at the hMC5R (EC50 = 0.072 nM and 0.031 nM, respectively), but full antagonists at the hMC3R and the hMC4R. We also demonstrated that the relative stereochemistry of the amino acid at the 6-position is critical for activity, and could play an important role in potency as well as in selectivity for the melanocortin receptors.

Original languageEnglish
Pages (from-to)1075-1080
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number4
Publication statusPublished - 2002
Externally publishedYes

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