Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist

Olivier Van Der Poorten, Krisztina Fehér, Koen Buysse, Debby Feytens, Ioanna Zoi, Steven D. Schwartz, José C. Martins, Dirk Tourwé, Minying Cai, Victor J. Hruby, Steven Ballet

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


To address the need for highly potent, metabolically stable, and selective agonists, antagonists, and inverse agonists at the melanocortin receptor subtypes, conformationally constrained indolo- and benzazepinone residues were inserted into the α-MSH pharmacophore, His6-Phe7-Arg8-Trp9-domain. Replacement of His6 by an aminoindoloazepinone (Aia) or aminobenzazepinone (Aba) moiety led to hMC4R and hMC5R selective agonist and antagonist ligands, respectively (tetrapeptides 1 to 3 and 4, respectively). In peptides 1 to 3 and depending on the para-substituent of the d-Phe residue in position 2, the activity goes from allosteric partial agonism (1, R = H) to allosteric full agonism (2, R = F) and finally allosteric partial agonism (3, R = Br).

Original languageEnglish (US)
Pages (from-to)192-197
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number2
StatePublished - Feb 12 2015


  • Melanocortin ligands
  • allosteric hMC4R ligands
  • constrained aminoazepinones
  • fluorine peptidomimetics
  • hMC4R and hMC5R molecular modeling and ligand docking

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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