Setmelanotide is a cyclic peptide agonist of melanocortin receptor 4 (MC4R).¹It increases cAMP production in CHO-K1 cells expressing MC4R, MC1R, MC3R, and MC5R (EC₅₀s = 0.27, 5.8, 5.3, and 1,600 nM, respectively, for the human receptors) but not in cells expressing MC2R (EC₅₀= >10 µM). Setmelanotide (6.4 µmol/animal) inhibits food intake in MC3R, but not MC4R, knockout mice. It also reduces food intake and hepatosteatosis, induces weight loss, and decreases serum insulin, glucose, and leptin levels in a mouse model of diet-induced obesity when administered at a dose of 300 nmol/kg per day. Formulations containing setmelanotide have been used in chronic weight management due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor deficiency.

1.Kumar, K.G., Sutton, G.M., Dong, J.Z., et al.Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J micePeptides30(10)1892-1900(2009)