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

• Published in: ACS medicinal chemistry letters Vol. 6; no. 2; pp. 192 - 197
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.02.2015
• Subjects: Letter; hMC4R and hMC5R molecular modeling and ligand docking; allosteric hMC4R ligands; Melanocortin ligands; constrained aminoazepinones; fluorine peptidomimetics
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml500436s

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).