Selective, High Affinity Peptide Antagonists of α-Melanotropin Action at Human Melanocortin Receptor 4: Their Synthesis and Biological Evaluation in Vitro

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Abstract
Peptide Ac-Nle4-cyclo(5β→10ε)(Asp5-His6-d-(2‘)Nal7-Arg8-Trp9-Lys10)-NH2, compound 1, a cyclic derivative of α-melanotropin, is a nonselective high affinity antagonist at human melanocortin receptors 3 and 4, and an agonist at melanocortin receptors 1 and 5. To differentiate between the physiological functions of these receptors, antagonists with improved receptor selectivity are needed. In this study, analogues of compound 1 without Ac-Nle4 or His6 and/or the amino group of Asp5 were prepared and tested in binding assays and in functional assays on CHO cells expressing hMC3-5R. Several of these peptides were to be selective, high affinity hMC-4R antagonists. The most interesting was compound 10, named MBP10, cyclo(6β→10ε)(succinyl6-d-(2‘)Nal7-Arg8-Trp9-Lys10)-NH2, an antagonist (IC50 = 0.5 nM) with 125-fold selectivity over hMC-3R (and of >300-fold selectivity over MC-1RB). This compound had no agonist activity at hMC-3R or hMC-4R and only weak agonist activity at hMC-5R. Examination of the sequences of these new peptides revealed that the d-(2‘)Nal7-Arg8-Trp9 segment of peptide 1 forms the “essential core” required for high affinity and high selectivity of analogues of peptide 1 at hMC-4R, but the “extended core”, His6-d-(2‘)Nal7-Arg8-Trp9, is necessary for the maximum affinity for hMC-3R and hMC-5R.