4-Norleucine, 7-d-phenylalanine-α-melanocyte-stimulating hormone: A highly potent α-melanotropin with ultralong biological activity

α-Melanocyte-stimulating hormone (α-MSH) reversibly darkens frog skins by stimulating melanosome movement (dispersion) within melanophores. Heat-alkali treatment of α-MSH results in prolonged biological activity of the hormone. Quantitative gas chromatographic analysis of the hydrolyzed heat-alkali-treated peptide revealed partial racemization particularly at the 4 (methionine) and 7 (phenylalanine) positions. [Nle ⁴]-α-MSH, a synthetic analogue of α-MSH, reversibly darkens frog skins and also exhibits prolonged activity after heat-alkali treatment. Synthesis of [Nle ⁴, D-Phe ⁷]-α-MSH provided an analogue with prolonged biological activity, identical to that observed with heat-alkali-treated α-MSH or [Nle ⁴]-α-MSH. [Nle ⁴, D-Phe ⁷]-α-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 melanoma adenylate cyclase, and stimulation of mouse melanoma cell tyrosinase activity. This Nle ⁴, D-Phe ⁷ synthetic analogue of α-MSH is a very potent melanotropin, 26 times as potent as α-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 analogue of α-MSH an important molecular probe for studying the melanotropin receptors of both normal and abnormal (melanoma) melanocytes.