Rates of obesity have steadily increased in the United States, with approximately 50 percent of Americans projected to be classified as obese by 2030. Interestingly, obesity even seems to be a risk factor for the severity of illness in response to COVID-19 disease. Although behavioral (dieting and exercise), pharmacological, and surgical approaches exist for weight loss, many individuals who lose weight are unable to sustain this weight loss due to compensatory behavioral, autonomic, and neuroendocrine pathways promoting rebound weight gain. Pathways preventing these compensatory adaptations would provide a wholly novel approach to the challenges of obesity treatment. The melanocortin-4 receptor (MC4R) agonist drug setmelanotide is highly effective in the treatment of rare obesity syndromes such as POMC and leptin deficiency, or Bardet-Biedl syndrome, but lacks adequate potency in dietary obesity. More potent MC4R agonists have demonstrated an unacceptable target-mediated pressor response. Recently, we demonstrated the melanocortin-3 receptor (MC3R) is a negative regulator of a subset of MC4R neurons by virtue of its activities in AgRP neurons, and thus is a novel target for development of obesity therapeutics. Two advantages of MC3R as a target are 1) MC3R has less pressor liability than MC4R, and 2) MC3R has been demonstrated to be required for the compensatory behavioral and neuroendocrine responses mediating weight regain following fasting and caloric restriction. Here, we show that a recently published MC3R antagonist, compound 11 (C11) produces profound 24hr inhibition of feeding, and weight loss, that is dependent on the MC3R. In this application we design a panel of melanocortin peptides (Aim 1), and test the modified analogues for improved receptor-subtype specificity and potency as MC3R antagonists (Aim 2), to advance through a process of lead optimization from tool compound C11 to MC3R peptide antagonist development candidates. The product of this Phase I STTR will be one or more patentable MC3R antagonist lead development candidates that can go into animal testing and advanced ADME/PK as a novel proprietary class of obesity therapeutics (Phase II). Success in Phase I will enable Courage Therapeutics to seek institutional funding, in advance of human clinical trials following a successful Phase II.