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

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

Olivier Van der Poorten et al. ACS Med Chem Lett.

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).

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

Figures

Figure 1
Figure 1
[Aba]MT-II analogues Aba-2–4 and the linear equivalent Aba-1.
Figure 2
Figure 2
Locally constrained melanocortin tetrapeptides 15, containing the Aia (1–3), Aba (4), and Ata (5) scaffolds.
Figure 3
Figure 3
Combined docking poses for Aia peptide 2 (magenta, calculated affinity: −10.8 kcal/mol), Aba peptide 4 (purple, calculated affinity: −10.0 kcal/mol), and [Nle4,d-Phe7]-α-MSH (dark brown) in hMC4R. Extracellular part of TMH4 (green helix) and -5 (yellow helix) are hidden for better visibility of the poses.
Figure 4
Figure 4
Best docking pose for (A) [Nle4,d-Phe7]-α-MSH (dark brown), (B) Aia peptide 2 (magenta), and (C) Aba peptide 4 (purple) in hMC4R. Extracellular part of TMH4 (green helix) and -5 (yellow helix) are hidden for better visibility of the poses.
Figure 5
Figure 5
Combined docking poses for Aia peptide 2 (magenta, calculated affinity: −8.0 kcal/mol) and Aba peptide 4 (purple, calculated affinity: −9.4 kcal/mol) in hMC5R. Extracellular part of TMH4 (green helix) and -5 (yellow helix) are hidden for better visibility of the poses.

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