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

Victor J. Hruby, Tomi K. Sawyer, Young C.S. Yang, Marvin D. Bregman, Mac E. Hadley, Christopher B. Heward

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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]-βp-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]-βp-MSH (5.2) [Nle4]-α-MSH (2.3)> α-MSH (1.0)> [Phe2,Nle4]-α-MSH (0.80)> βP-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]-βp-MSH (4.2)> βP-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.

Original languageEnglish (US)
Pages (from-to)1432-1437
Number of pages6
JournalJournal of Medicinal Chemistry
Volume23
Issue number12
DOIs
StatePublished - Dec 1 1980

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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