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. 2006 Feb;27(2):472-81.
doi: 10.1016/j.peptides.2005.01.032. Epub 2005 Nov 21.

Structure-activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

Paolo Grieco  1 , Minying Cai, Alexander V Mayorov, Dev Trivedi, Victor J Hruby
Affiliations

Structure-activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

Paolo Grieco et al. Peptides. 2006 Feb.

Abstract

Cyclic melanotropin peptides, designed with an aromatic amino acid substitution at the N-terminal position of the MT-II-type scaffold, were prepared by solid-phase peptide synthesis and evaluated for their ability to bind to and activate human melanocortin-1, -3, -4, and -5 receptors. The structure-activity studies of these MT-II analogues have identified a selective antagonist at the hMC4R (H-Phe-c[Asp-Pro-d-Nal(2')-Arg-Trp-Gly-Lys]-NH(2), pA(2)=8.7), a selective partial agonist at the hMC4R (H-d-Nal(2')-c[Asp-Pro-d-Phe-Arg-Trp-Gly-Lys]-NH(2), IC(50)=11nM, EC(50)=56nM), and a selective partial agonist at the hMC3R (H-d-Phe-c[Asp-Pro-d-Phe-Arg-Trp-Lys]-NH(2), IC(50)=3.7nM, EC(50)=4.9nM). Aromatic amino acid substitution at the N-terminus in conjuction with the expansion of the 23-membered cyclic lactam MT-II scaffold to a 26-membered scaffold by addition of a Gly residue in position 10 leads to melanotropin peptides with enhanced receptor selectivity.

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Figures

Fig. 1
Fig. 1
Stereoview of the superimposed LLMOD-derived global minima of PG-137 [red: black (print version)] and PG-933 [blue: grey (print version)] (rmsd = 0.91 Å). “For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article”.
Fig. 2
Fig. 2
Stereoview of the superimposed NMR conformation of core sequence His-d-Phe-Arg-Trp of MT-II [red: black (print version)] [44] and the LLMOD-derived global minimum of the core sequence Pro-d-Nal(2′)-Arg-Trp of PG-138 [blue: grey (print version)] (rmsd = 1.27 Å). “For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article”.
Fig. 3
Fig. 3
Stereoview of the superimposed NMR structure of MT-II [red: black (print version)] [44] and the LLMOD-derived global minimum of PG-951 [blue: grey (print version)] (rmsd = 0.77 Å). The Lys residues and the side chains of Asp5 are omitted for clarity. “For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article”.
See this image and copyright information in PMC

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