Further structure-activity studies of lactam derivatives of MT-II and SHU-9119: Their activity and selectivity at human melanocortin receptors 3, 4, and 5

Paolo Grieco, Minying Cai, Guoxia Han, Dev Trivedi, Pietro Campiglia, Ettore Novellino, Victor J. Hruby

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1191-1196
Number of pages6
JournalPeptides
Volume28
Issue number6
DOIs
StatePublished - Jun 2007

Keywords

  • Cyclic melanotropins
  • Melanocortin receptors
  • Melanotropins
  • Receptor selective melanotropin antagonists
  • Structure-activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

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