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

ACS Med Chem Lett. 2014 Dec 29;6(2):123-7. doi: 10.1021/ml500340z.

Skye R Doering ¹, Aleksandar Todorovic ², Carrie Haskell-Luevano ³

Affiliations

1 Department of Medicinal Chemistry, University of Minnesota , Twin Cities, Minnesota 55455, United States.
2 Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.
3 Department of Medicinal Chemistry, University of Minnesota , Twin Cities, Minnesota 55455, United States ; Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.

PMID: 25699138 DOI: 10.1021/ml500340z

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.

Keywords

Melanotropin; feeding behavior; obesity; probe; solid phase synthesis.

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