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

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

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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.

Original languageEnglish (US)
Pages (from-to)27656-27663
Number of pages8
JournalACS Omega
Issue number31
StatePublished - Aug 9 2022

Bibliographical note

Funding Information:
The work was supported by the National Institutes of Health grant R01DK123504 (C.H.-L.) and the Helmholtz Institut für Metabolismus, Adipositas und Gefäßforschung (HIMAG111) (A.G.). A.G. thanks the DFG for continuous support.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

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