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

The synthesis and purification of several analogues of the melanotropins with amino acid substitutions at the tyrosine-2 and methionine-4(7) positions are reported. The compounds synthesized included [4-norleucine]-α-MSH, [7-norleucine]-β_p-MSH, [2-3ʹ,5ʹ-diiodotyrosine]-α-MSH, [2-D-tyrosine]-α-MSH, and [2-phenylalanine, 4-norleucine]-α-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 (α-MSH = 1.0) were as follows: [Nle⁷]-β_p-MSH (5.2) [Nle⁴]-α-MSH (2.3)> α-MSH (1.0)> [Phe²,Nle⁴]-α-MSH (0.80)> β_P-MSH (0.55)> [I₂-Tyr²]-α-MSH (0.12)> [D-Tyr²]-α-MSH (0.04). The relative potencies in the melanoma adenylate cyclase system were [Nle⁷]-β_p-MSH (4.2)> β_P-MSH (2.2)> [Nle⁴]-α-MSH (2.0)> α-MSH (1.0) ≈ [Phe²,Nle⁴]-α-MSH (0.9) [I₂-Tyr²]-α-MSH (0.40) [D-Tyr²]-α-MSH (0.20). There appears to be some differences in structural specificity at the melanotropin receptors of the two cell systems.