[half-Cys4,half-Cys10]-α -Melanocyte-Stimulating Hormone: A Cyclic α -melanotropin Exhibiting Superagonist Biological Activity

α -Melanocyte-stimulating hormone (α -melanotropin; α -MSH) is a linear tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) that reversibly darkens amphibian skins by stimulating melanosome (pigment granule) dispersion within melanophores. By using a number of in vitro melano...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1982-03, Vol.79 (6), p.1751-1755
Main Authors: Sawyer, Tomi K., Hruby, Victor J., Darman, Paul S., Hadley, Mac E.
Format: Article
Language:English
Subjects:
Adenylyl Cyclases - metabolism
alpha-MSH - analogs & derivatives
Amino acids
Amphibians
Animals
Biochemistry
Biological pigments
Cells, Cultured
Cyclic AMP - biosynthesis
Hormones
Hormones - pharmacology
Melanocyte-Stimulating Hormones - analogs & derivatives
Melanocyte-Stimulating Hormones - pharmacology
Melanoma
Melanophores
Melanophores - drug effects
Melanosomes
Protein Conformation
Rana pipiens
Receptors
Reptiles
Resins
Structure-Activity Relationship
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Summary:α -Melanocyte-stimulating hormone (α -melanotropin; α -MSH) is a linear tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) that reversibly darkens amphibian skins by stimulating melanosome (pigment granule) dispersion within melanophores. By using a number of in vitro melanocyte assays, we have examined the conformational requirements for α -MSH activity. Synthesis of [half-Cys4,half-Cys10]-α -MSH, a cyclic, conformationally restricted, ``isosteric'' analogue of α -MSH, provided a melanotropin with a potency > 10,000 times that of the native hormone in stimulating frog (Rana pipiens) skin darkening. The cyclic analogue also showed substantially prolonged activity relative to the native hormone. [half-Cys4, half-Cys10]-α -MSH was ≈ 30 times more potent than α -MSH in stimulating lizard (Anolis carolinensis) skin melanophores in vitro. By using a cell-free Cloudman S-91 mouse melanoma plasma membrane preparation, we found the cyclic analogue to be ≈ 3 times as potent as the native hormone in stimulating adenylate cyclase activity. These results provide insight into the conformational requirements for biological activity of α -MSH, and the comparative conformational requirements of α -MSH at a number of pigment cell receptors.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.79.6.1751