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Review
. 2019 May 16;24(10):1892.
doi: 10.3390/molecules24101892.

Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Shubh Sharma  1 , Alastair S Garfield  2 , Bhavik Shah  3 , Patrick Kleyn  4 , Ilia Ichetovkin  5 , Ida Hatoum Moeller  6 , William R Mowrey  7 , Lex H T Van der Ploeg  8
Affiliations
Review

Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Shubh Sharma et al. Molecules. .

Abstract

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.

Keywords: GαS signaling; cardiovascular profile; melanocortin-4 receptor; obesity; peptide agonist; receptor desensitization; receptor internalization.

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Conflict of interest statement

All authors are employees of Rhythm Pharmaceuticals.

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