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. 2022 Jul 29;7(31):27656-27663.
doi: 10.1021/acsomega.2c03307. eCollection 2022 Aug 9.

Incorporation of Indoylated Phenylalanine Yields a Sub-Micromolar Selective Melanocortin-4 Receptor Antagonist Tetrapeptide

Mark D Ericson  1 , Courtney M Larson  1 , Katie T Freeman  1 , Lennart Nicke  2 , Armin Geyer  2 , Carrie Haskell-Luevano  1
Affiliations

Incorporation of Indoylated Phenylalanine Yields a Sub-Micromolar Selective Melanocortin-4 Receptor Antagonist Tetrapeptide

Mark D Ericson et al. ACS Omega. .

Abstract

The melanocortin family is involved in many physiological functions, including pigmentation, steroidogenesis, and appetite. The centrally expressed melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R) possess overlapping but distinct roles in energy homeostasis. Herein, the third and fourth positions of a tetrapeptide lead compound [Ac-Arg-Arg-(pI)DPhe-Tic-NH2], previously reported to possess MC3R agonist and MC4R antagonist activities, were substituted with indoylated phenylalanine (Wsf/Wrf) residues in an attempt to generate receptor subtype selective compounds. At the third position, d-amino acids were required for melanocortin agonist activity, while both l- and d-residues resulted in MC4R antagonist activity. These results indicate that l-indoylated phenylalanine residues at the third position of the scaffold can generate MC4R over MC3R selective antagonist ligands, resulting in a substitution pattern that may be exploited for novel MC4R ligands that can be used to probe the in vivo activity of the MC4R without involvement of the MC3R.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Structures of the indoylated phenylalanine amino acids used in this study. β-indoylation of Phe or β-phenylation of Trp yields the four β-branched α-amino acids Wrf, Wsf, wrf, and wsf, wherein the first letter of the three-letter code of the β-indoylated amino acids stands for l- or d-tryptophan (W or w), the second for either R- or S- stereochemistry of Cβ, and the third letter for phenylalanine. The Newman plot shows the rotamer occupied by Wrf with the phenyl ring exclusively in an antiperiplanar orientation, relative to the carbonyl group (χ1 = CO-Cα-Cβ-Cγphenyl = 180°). (b) Tic tethers the phenyl group to two out of three χ1 rotamers accessible for Phe, which are shown below in (c).
Figure 2
Figure 2
Illustration of the agonist pharmacology of NDP-MSH, 1, 3, 5, and 7 at the mMC1R, mMC3R, mMC4R, and mMC5R.
Figure 3
Figure 3
Illustration of the antagonist pharmacology of 7 at the mMC1R, mMC3R, mMC4R, and mMC5R.
See this image and copyright information in PMC

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