Melanocortin antagonist tetrapeptides with minimal agonist activity at the mouse melanocortin-3 receptor

Skye R Doering, Aleksandar Todorovic, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The melanocortin system regulates many important functions in the body. There are five melanocortin G protein-coupled receptor subtypes known to date. Herein, we report a structure-activity relationship (SAR) study of a tetrapeptide lead discovered through a double substitution strategy at the melanocortin core His-Phe-Arg-Trp sequence. Several compounds were identified with micromolar agonist activity at the mouse melanocortin-1 (mMC1R) and mouse melanocortin-5 receptor (mMC5R) subtypes, weak antagonist activity at the mouse melanocortin-3 receptor (mMC3R), and potent antagonist activity at the mouse melanocortin-4 receptor (mMC4R). Two compounds (2 and 3) were nanomolar mMC4R antagonists with no mMC3R antagonist activity observed. Additionally, we identified three tetrapeptide MC3R antagonists (1, 6, and 7) that possess minimal mMC3R agonist activity only at 100 μM, not commonly observed for mMC3R/mMC4R antagonists. These novel molecular templates have the potential as molecular probes to better differentiate the roles of the centrally expressed MC3 and MC4 receptors.

Original languageEnglish (US)
Pages (from-to)123-127
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number2
DOIs
StatePublished - Feb 12 2015

Keywords

  • Melanotropin
  • feeding behavior
  • obesity
  • probe
  • solid phase synthesis

Fingerprint Dive into the research topics of 'Melanocortin antagonist tetrapeptides with minimal agonist activity at the mouse melanocortin-3 receptor'. Together they form a unique fingerprint.

Cite this