title: Azepinone-Containing Tetrapeptide Analogues of Melanotropin Lead to Selective hMC4R Agonists and hMC5R Antagonist.
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, His(6)-Phe(7)-Arg(8)-Trp(9)-domain. Replacement of His(6) 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).
authors.affiliation: Research Group of Organic Chemistry, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Van der Poorten
authors.affiliation: Department of Organic Chemistry, University of Ghent , Krijgslaan 281 S4, 9000 Ghent, Belgium.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Fehér
authors.affiliation: Research Group of Organic Chemistry, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Buysse
authors.affiliation: Research Group of Organic Chemistry, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Debby
authors.initials: D
authors.lastname: Feytens
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Zoi
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
authors.affiliation: Department of Organic Chemistry, University of Ghent , Krijgslaan 281 S4, 9000 Ghent, Belgium.
authors.forename: José C
authors.initials: JC
authors.lastname: Martins
authors.affiliation: Research Group of Organic Chemistry, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
authors.affiliation: Research Group of Organic Chemistry, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
keywords: Melanocortin ligands; allosteric hMC4R ligands; constrained aminoazepinones; fluorine peptidomimetics; hMC4R and hMC5R molecular modeling and ligand docking