Extensive structure - Activity studies of lactam derivatives of MT-II and SHU-9119

Their activity and selectivity at human melanocortin receptors 3, 4, and 5

P. Grieco, P. Balse-Srinivasan, G. Han, D. Weinberg, T. MacNeil, L. H T Van Der Ploeg, Victor J Hruby

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The melanocortin system is involved in the regulation of several diverse physiologic pathways. Recently we have demonstrated that replacing His 6 by Pro6 in the well-known antagonist SHU-9119 resulted in a potent agonist at the hMC5R (EC50 = 0.072 nM) with full antagonist activity at the hMC3R and the hMC4R. We have designed, synthesized, and pharmacologically characterized a series of peptide analogs of MT-11 and SHU-9119 at the human melanocortin receptors MC3R, MC4R and MC5R. All these peptides were modified at position 6 with a Pro instead of a His residue. In this study, we have identified new scaffolds which are antagonists at the hMC4R and hMC3R. Additionally, we have discovered a new selective agonist at the hMC4R, Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-Pro-Val-NH2 (6, PG-931) which will be useful in further biologic investigations of the hMC4R. PG-931 was about 100-fold more selective for the hMC4R vs. the hMC3R (IC50 = 0.58 and 55 nM, respectively). Some of these new analogs have exceptional biologic potencies at the hMC5R and 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)199-206
Number of pages8
JournalJournal of Peptide Research
Volume62
Issue number5
DOIs
StatePublished - Nov 2003

Fingerprint

Receptor, Melanocortin, Type 3
Receptor, Melanocortin, Type 4
Lactams
MT Peptide
His-His-His-His-His-His
Derivatives
Melanocortin Receptors
Melanocortins
Peptides
Scaffolds
Inhibitory Concentration 50
SHU 9119
melanocortin 5 receptor
Ac-Nle-c(Asp-Pro-D-Phe-Arg-Trp-Lys)-Pro-Val-NH2
human MC3R protein

Keywords

  • Melanotropins

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Extensive structure - Activity studies of lactam derivatives of MT-II and SHU-9119 : Their activity and selectivity at human melanocortin receptors 3, 4, and 5. / Grieco, P.; Balse-Srinivasan, P.; Han, G.; Weinberg, D.; MacNeil, T.; Van Der Ploeg, L. H T; Hruby, Victor J.

In: Journal of Peptide Research, Vol. 62, No. 5, 11.2003, p. 199-206.

Research output: Contribution to journalArticle

Grieco, P. ; Balse-Srinivasan, P. ; Han, G. ; Weinberg, D. ; MacNeil, T. ; Van Der Ploeg, L. H T ; Hruby, Victor J. / Extensive structure - Activity studies of lactam derivatives of MT-II and SHU-9119 : Their activity and selectivity at human melanocortin receptors 3, 4, and 5. In: Journal of Peptide Research. 2003 ; Vol. 62, No. 5. pp. 199-206.
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