title: [half-Cys4,half-Cys10]-alpha-Melanocyte-stimulating hormone: a cyclic alpha-melanotropin exhibiting superagonist biological activity.
abstract: alpha-Melanocyte-stimulating hormone (alpha-melanotropin; alpha-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 melanomsome (pigment granule) dispersion within melanophores. By using a number of in vitro melanocyte assays, we have examined the conformational requirements for alpha-MSH activity. Synthesis of [half-Cys4,half-Cys10]-alpha-MSH, a cyclic, conformationally restricted, "isosteric" analogue of alpha-MSH, provided a melanotropin with a potency greater than 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]-alpha-MSH was approximately 30 times more potent than alpha-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 approximately 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 alpha-MSH, and the comparative conformational requirements of alpha-MSH at a number of pigment cell receptors.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D006728:Hormones / Q000494:pharmacology; D009074:Melanocyte-Stimulating Hormones / Q000031:analogs & derivatives* / Q000494:pharmacology; D008547:Melanophores / Q000187:drug effects; D011487:Protein Conformation; D011894:Rana pipiens; D012104:Reptiles; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives*
chemical_list: D006728:Hormones; C034542:MSH, 4-half-Cys-10-half-Cys-alpha-; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP; D000262:Adenylyl Cyclases