Multimeric Alpha-Msh Has Increased Efficacy to Activate the Melanocortin Mc4 Receptor

α-Melanocyte stimulating hormone (α-MSH) has a relatively low affinity for the melanocortin MC4 receptor. Constructs of multimeric α-MSH varying from one to eight subunits were synthesized to test whether they displayed an improved ability to bind to and activate the human melanocortin MC4 receptor. α-MSH subunits were coupled by a flexible linker and placed in front of an IRES-eGFP sequence. Efficacy for activation of the melanocortin MC4 receptor increased with every extra subunit, resulting in a 100 fold lower EC50 value of α-MSH8 when compared with α-MSH1. Furthermore, supernatant of cells transfected with α-MSH8 proved to have an increased affinity to the melanocortin MC4 receptor when compared to cells transfected with the other multimers. Together, these data show that multimeric α-MSH has improved ability to activate the human melanocortin MC4 receptor in vitro.