Azepinone-Containing Tetrapeptide Analogues of Melanotropin Lead to Selective hMC4R Agonists and hMC5R Antagonist

作者：Van der Poorten Olivier; Feher Krisztina; Buysse Koen; Feytens Debby; Zoi Ioanna; Schwartz Steven D; Martins Jose C; Tourwe Dirk; Cai Minying; Hruby Victor J; Ballet Steven^*

来源：ACS Medicinal Chemistry Letters, 2015, 6(2): 192-197.

DOI：10.1021/ml500436s

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

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 alpha-MSH pharmacophore, His(6)-Phe(7)-Arg(8)-Trp(9)-domain. Replacement of His(6) by an aminoindoloazepinone (Ala) 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 n-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).

• 出版日期2015-2