4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity.

Abstract

.alpha.-Melanocyte-stimulating hormone (.alpha.-MSH) reversibly darkens frog skins by stimulating melanosome movement (dispersion) within melanophores. Heat-alkali treatment of .alpha.-MSH results in prolonged biological activity of the hromone. Quantitative gas chromatographic analysis of the hydrolyzed heat-alkali-treated peptide revealed partial racemization particularly at the 4 (methionine) and 7 (phenylalanine) positions. [Nle4]-.alpha.-MSH, a synthetic analog of .alpha.-MSH, reversibly darkens frog skins and also exhibits prolonged activity after heat-alkali treatment. Synthesis of [Nle4, D-Phe7]-.alpha.-MSH provided an analog with prolonged biological activity, identical to that observed with heat-alkali-treated .alpha.-MSH or [Nle4]-.alpha.-MSH. [Nle4,D-Phe7]-.alpha.-MSH was resistant to enzymatic degradation by serum enzymes. In addition, this peptide exhibited dramatically increased biological activity as determined by frog skin bioassay, activation of mouse [S-91] melanoma adenylate cyclase and stimulation of mouse melanoma cell tyrosinase activity. This Nle4,D-Phe7 synthetic analog of .alpha.-MSH is a very potent melanotropin, 26 times as potent as .alpha.-MSH in the adenylate cyclase assay. The resistance of the peptide to enzymatic degradation and its extraordinarily potent and prolonged biological activity should make this analog of .alpha.-MSH an important molecular probe for studying the melonotropin receptors of both normal and abnormal (melanoma) melanocytes.