TY - JOUR
T1 - Further structure-activity studies of lactam derivatives of MT-II and SHU-9119
T2 - Their activity and selectivity at human melanocortin receptors 3, 4, and 5
AU - Grieco, Paolo
AU - Cai, Minying
AU - Han, Guoxia
AU - Trivedi, Dev
AU - Campiglia, Pietro
AU - Novellino, Ettore
AU - Hruby, Victor J.
N1 - Funding Information:
This research was supported primarily by the U.S. Public Health Service, National Institute of Health, DK17420 and DA06284.
PY - 2007/6
Y1 - 2007/6
N2 - Recently we have demonstrated that replacing His6 by constrained amino acids22Amino acid symbols denote L-configuration unless indicated otherwise. in the well-known antagonist SHU-9119 resulted in potent and selective antagonist ligands especially at the hMC3R and hMC5 receptors. With the aim to further explore position 6 in the sequence of SHU-9119 and MT-II, we have designed, synthesized, and pharmacologically characterized a series of peptide analogues of MT-II and SHU-9119 at the human melanocortin receptors subtypes MC3R, MC4R and MC5R. All these peptides were modified at position 6 with constrained amino acids which are commercially available. In this study, we have identified new selective ligands for the hMC4R, and an antagonist for the hMC3/hMC4 receptors. Additionally, we have discovered an interesting new selective antagonist at the hMC3R, Ac-Nle-c[Asp-βAla-DNal(2′)-Arg-Trp-Lys]-NH2 (2, PG-106) which represents an important tool in further biological investigations of the hMC3R. PG-106 will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.
AB - Recently we have demonstrated that replacing His6 by constrained amino acids22Amino acid symbols denote L-configuration unless indicated otherwise. in the well-known antagonist SHU-9119 resulted in potent and selective antagonist ligands especially at the hMC3R and hMC5 receptors. With the aim to further explore position 6 in the sequence of SHU-9119 and MT-II, we have designed, synthesized, and pharmacologically characterized a series of peptide analogues of MT-II and SHU-9119 at the human melanocortin receptors subtypes MC3R, MC4R and MC5R. All these peptides were modified at position 6 with constrained amino acids which are commercially available. In this study, we have identified new selective ligands for the hMC4R, and an antagonist for the hMC3/hMC4 receptors. Additionally, we have discovered an interesting new selective antagonist at the hMC3R, Ac-Nle-c[Asp-βAla-DNal(2′)-Arg-Trp-Lys]-NH2 (2, PG-106) which represents an important tool in further biological investigations of the hMC3R. PG-106 will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.
KW - Cyclic melanotropins
KW - Melanocortin receptors
KW - Melanotropins
KW - Receptor selective melanotropin antagonists
KW - Structure-activity relationships
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U2 - 10.1016/j.peptides.2007.02.012
DO - 10.1016/j.peptides.2007.02.012
M3 - Article
C2 - 17482720
AN - SCOPUS:34249736864
SN - 0196-9781
VL - 28
SP - 1191
EP - 1196
JO - Peptides
JF - Peptides
IS - 6
ER -