TY - JOUR
T1 - Design and synthesis of highly potent and selective melanotropin analogues of SHU9119 modified at position 6
AU - Grieco, Paolo
AU - Han, Guoxia
AU - Hruby, Victor J.
AU - Weinberg, David
AU - Van der Ploeg, L. H.T.
N1 - Funding Information:
This research was supported in part by grants from the U.S. Public Health Service, DK-17420 and from Merck Research Laboratories. The opinions expressed are those of the authors and not necessarily of the U.S. Public Health Service.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036283824&partnerID=8YFLogxK
U2 - 10.1006/bbrc.2002.6739
DO - 10.1006/bbrc.2002.6739
M3 - Article
C2 - 11944925
AN - SCOPUS:0036283824
SN - 0006-291X
VL - 292
SP - 1075
EP - 1080
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -