Preparation of human Melanocortin-4 receptor agonist libraries: Linear peptides X-Y-DPhe7-Arg8-Trp(or 2-Nal)9-Z-NH2

Two libraries of hMC4R agonists, X-Y-DPhe7-Arg8-2-Nal9-Z-NH2 and X-Y-DPhe7-Arg8-Trp9-Z-NH2, totaling 185 peptides were prepared using Irori radiofrequency tagging technology and Argonaut Quest 210 Synthesizer, where X stands for N-caps, Y for His6 surrogates and Z for Gly10 surrogates. As a result of this study, His-modified pentapeptides with Trp were found to be more hMC4R potent than the corresponding 2-Nal analogs, novel N-caps and Gly surrogates were identified and 19 new peptides which are potent hMC4R agonists (EC50 1–15 nM) and selective against hMC1R were discovered.