Structure–Activity relationship of linear peptide Bu-His-DPhe-Arg-Trp-Gly-NH2 at the human melanocortin-1 and -4 receptors: arginine substitution

A series of pentapeptides, based on Bu-His6-DPhe7-Arg8-Trp9-Gly10-NH2 and modified at the Arg8 position, was prepared and pharmacologically characterized. Peptides containing either cyanoguanidine or acylguanidine, two substantially less basic arginine surrogates, were found to retain the agonist activity of the parent peptide at both hMC1R and hMC4R. This study unequivocally shows that the positive charge of Arg8 is not essential for efficient interactions of our pentapeptide with both hMC1R and hMC4R.