Synthesis and structure-function studies of melanocyte stimulating hormone analogues 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]-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) approximately equal to [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 two cell systems.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D009074:Melanocyte-Stimulating Hormones / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology*; D008547:Melanophores / Q000187:drug effects*; D009374:Neoplasms, Experimental / Q000201:enzymology; D011898:Ranidae; D012867:Skin / Q000187:drug effects
D009074:Melanocyte-Stimulating Hormones; D000262:Adenylyl Cyclases