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. 2019 Apr 13;24(8):1463.
doi: 10.3390/molecules24081463.

Structure⁻Activity Relationships of the Tetrapeptide Ac-His-Arg-(p I)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (p I)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands

Katherine N Schlasner  1 , Mark D Ericson  2 , Skye R Doering  3 , Katie T Freeman  4 , Mary Weinrich  5 , Carrie Haskell-Luevano  6
Affiliations

Structure⁻Activity Relationships of the Tetrapeptide Ac-His-Arg-(p I)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (p I)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands

Katherine N Schlasner et al. Molecules. .

Abstract

The five melanocortin receptors (MC1R-MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.

Keywords: MC3R; MC4R; melanocortins; mixed pharmacology; tetrapeptides.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures and abbreviations of the amino acids used to replace the third amino acid in the peptide template Ac-His-Arg-Xxx-Tic-NH2.
Figure 2
Figure 2
Illustration of the agonist pharmacology of NDP-MSH, KNS2-153, KNS2-22-1, KNS3-10, KNS2-23-3, and KNS2-23-8 at the mMC3R and mMC4R.
Figure 3
Figure 3
Illustration of the antagonist pharmacology of KNS2-22-4 and KNS2-23-8 at the mMC4R.
See this image and copyright information in PMC

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