Summary of the structure-activity relationship observed for this octapeptide scaffold at the mMC4R, as published previously.46, 56 In this figure, the sequence of the lead scaffold is shown in the black bar. Below each position is a listing of the different substitutions that have been tested at that position with a color scheme. Compounds containing substitutions shown in green possess increased potency compared to the lead scaffold, compounds containing substitutions shown in black are equipotent to the lead scaffold, compounds containing substitutions shown in blue possess decreased potency compared to the lead scaffold, and compounds possessing substitutions shown in red did not possess antagonist potency that could be observed at the highest concentrations used in that assay. The studies examining the Phe3, Phe4, and Asn5 positions utilize unnatural amino acids, and the structures of the amino acids are provided and colored as described above.