INVESTIGATING THE STRUCTURAL CHARACTERISTICS OF AN hMC4R SELECTIVE AGONIST

Abstract

The melanocortin receptors are a family of five G-protein coupled receptors, MC1R-MC5R. Recently, it was discovered that inhibition of MC4R impairs cognitive function in Alzheimer’s mice models. Furthermore, activation of MC4R in these mice rescues cognitive function. As a result, MC4R may be a potential drug target to treat Alzheimer’s disease. One of the main obstacles that presents itself is that MC1R, MC3R, MC4R, and MC5R are activated by one of three melanocortin stimulating hormones (MSH); α-MSH, β-MSH, and γ-MSH. Because of this, designing selective, potent agonists has been difficult. To better understand the structural characteristics that lead to MC4R selectivity, nine novel peptides were created, AIM 1-AIM 9. These peptides were made by modifying the sequence of MT-II, a synthetic agonist of all receptors except MC2R. The modifications made were chosen because of their ability to increase MC4R selectivity or decrease selectivity at other receptors. To test their selectivity, cAMP activity assays was performed on each receptor, and the EC50 values were compared to MT-II. Careful pharmacological analysis demonstrated that the compound AIM 9 has high selectivity for the MC4R with an EC50 of 4nM.