Discovery of Polypharmacological Melanocortin-3 and -4 Receptor Probes and Identification of a 100-Fold Selective nM MC3R Agonist versus a μm MC4R Partial Agonist

Katlyn A. Fleming, Katie T. Freeman, Mike D. Powers, Radleigh G. Santos, Ginamarie Debevec, Marc A. Giulianotti, Richard A. Houghten, Skye R. Doering, Clemencia Pinilla, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The centrally expressed melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R, respectively) are established targets to treat diseases of positive- and negative-energy homeostasis. We previously reported [ Doering, S. R.; et al. J. Med. Chem. 2017, 60, 4342-4357 ] mixture-based positional scanning approaches to identify dual MC3R agonist and MC4R antagonist tetrapeptides. Herein, 46 tetrapeptides were chosen for MC3R agonist screening selectivity profiles, synthesized, and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. Substitutions to the tetrapeptide template were selected solely based on MC3R agonist potency from the mixture-based screen. This study resulted in the discovery of compound 42 (Ac-Val-Gln-(pI)DPhe-DTic-NH2), a full MC3R agonist that is 100-fold selective for the MC3R over the μM MC4R partial agonist pharmacology. This compound represents a first-in-class MC3R selective agonist. This ligand will serve as a useful in vivo molecular probe for the investigation of the roles of the MC3R and MC4R in diseases of dysregulated energy homeostasis.

Original languageEnglish (US)
Pages (from-to)2738-2749
Number of pages12
JournalJournal of medicinal chemistry
Volume62
Issue number5
DOIs
StatePublished - Mar 14 2019

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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