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ACS Med Chem Lett. 2014 Dec 3;6(2):192-7. doi: 10.1021/ml500436s. eCollection 2015 Feb 12.

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

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Research Group of Organic Chemistry, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
Department of Organic Chemistry, University of Ghent , Krijgslaan 281 S4, 9000 Ghent, Belgium.
Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.


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).


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

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