Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor

Hongchang Qu, Minying Cai, Alexander V. Mayorov, Paolo Grieco, Morgan Zingsheim, Dev Trivedi, Victor J. Hruby

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

A new series of melanotropin analogues with His or Arg residues in the core pharmacophores of MTII, SHU9119, and Ac-NDP-γ-MSH-NH2 replaced by Pro or trans-/cis-4-guanidinyl-Pro derivatives were designed and synthesized to introduce selectivity toward the human melanocortin 4 receptor (hMC4R). Analogues 1, 2, 3, 6, 7, 8 were found to be hMC4R selective. Second messenger studies have demonstrated that analogues 1 and 2 are insurmountable inhibitors of MTII agonist activity at the hMC4R. Molecular modeling studies suggest that the hMC4R selectivity is due to a β-turn shift induced by the Pro ring that makes the global minimum structures of these analogues resemble the NMR solution structure of the hASIP melanocortin receptor binding motif. Substitution of His in MTII also provided functional selectivity for the hMC3R or the hMC4R. These findings are important for a better understanding of the selectivity mechanism at the hMC3R/hMC4R and the development of therapeutic ligands selectively targeting the hMC4R.

Original languageEnglish (US)
Pages (from-to)3627-3635
Number of pages9
JournalJournal of Medicinal Chemistry
Volume52
Issue number12
DOIs
StatePublished - Jun 25 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor'. Together they form a unique fingerprint.

  • Cite this