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 journalArticle

6 Citations (Scopus)

Abstract

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
Volume6
Issue number2
DOIs
StatePublished - Feb 12 2015

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Melanocortin Receptors
Melanocyte-Stimulating Hormones
Ligands
Peptides

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist. / Van Der Poorten, Olivier; Fehér, Krisztina; Buysse, Koen; Feytens, Debby; Zoi, Ioanna; Schwartz, Steven D; Martins, José C.; Tourwé, Dirk; Cai, Minying; Hruby, Victor J; Ballet, Steven.

In: ACS Medicinal Chemistry Letters, Vol. 6, No. 2, 12.02.2015, p. 192-197.

Research output: Contribution to journalArticle

Van Der Poorten, Olivier ; Fehér, Krisztina ; Buysse, Koen ; Feytens, Debby ; Zoi, Ioanna ; Schwartz, Steven D ; Martins, José C. ; Tourwé, Dirk ; Cai, Minying ; Hruby, Victor J ; Ballet, Steven. / Azepinone-containing tetrapeptide analogues of melanotropin lead to selective h MC4R agonists and h MC5R antagonist. In: ACS Medicinal Chemistry Letters. 2015 ; Vol. 6, No. 2. pp. 192-197.
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