A Ligand Template That Functionally Corrects Eleven Melanocortin-4 Receptor (Mc4r) Polymorphisms

The MC4R is a G-protein coupled receptor(GPCR) expressed in the brain, and has a role in regulating food intake and obesity. We have pharmacologically characterized eleven reported human MC4R polymorphisms in vitro that do not respond normally to the endogenous agonists a-MSH, b-MSH, g2-MSH, ACTH(1–24), but are expressed at the cell surface. The agonist ligand AMW3-130 possess a sub-nM stimulatory potency at these dysfunctional hMC4Rs. Central administration of a derivative of AMW3-130 into ad libium fed cannulated mice resulted in a statistically significant decrease in food intake, with no observed adverse behavior. These data are in agreement with the role of an MC4R agonist to decrease food intake. This is the first report we are aware of, identifying a ligand that can correct for functional defects of hMC4R polymorphic receptors and provides a potential lead therapeutic agent to treat children and adults with these mutations to increase their quality of life. This work has been supported by NIH Grants R01DK063974, R01DK57080, R01DK64250, and an American Diabetes Association Research Award (CHL).