Synthesis and structure-function studies of melanocyte stimulating hormone analogs modified in the 2 and 4(7) positions: comparison of activities on frog skin melanophores and melanoma adenylate cyclase

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Abstract
The synthesis and purification of several analogs of the melanocyte stimulating hormones [melanotropins, MSH] with amino acid substitutions at the tyrosine-2 and methionine-4(7) positions are reported. The compounds synthesized included [4-norleucine]-.alpha.-MSH, [7-norleucine]-.beta.p-MSH, [2-3'',5''-diiodotyrosine]-.alpha.-MSH, [2-D-tyrosine]-.alpha.-MSH and [2-phenylalanine,4-norleucine]-.alpha.-MSH. The biological activities of these derivatives were measured and compared on normal melanocytes (frog skins) and on transformed melanocytes (mouse melanoma adenylate cyclase), over the entire dose-response range. All compounds tested were full agonists in both assay systems but varied considerably in potency. The relative potencies in the frog skin assay (.alpha.-MSH = 1.0) were as follows: [Nle7]-.beta.p-MSH (5.2) > [Nle4]-.alpha.-MSH (2.3) > .alpha.-MSH (1.0) > [Phe2,Nle4]-.alpha.-MSH (0.80) > .beta.p-MSH (0.55) > [I2-Tyr2]-.alpha.-MSH (0.12) > [D-Tyr2]-.alpha.-MSH (0.04). The relative potencies in the melanoma adenylate cyclase system were [Nle7]-.beta.p-MSH (4.2) > .beta.p-MSH (2.2) > [Nle4]-.alpha.-MSH (2.0) > .alpha.-MSH (1.0) .apprxeq. [Phe2,Nle4]-.alpha.-MSH (0.9) > [I2-Tyr2]-.alpha.-MSH (0.40) > [D-Tyr2]-.alpha.-MSH (0.20). There appears to be some differences in structural specificity at the melanotropin receptors of the 2 cell systems.