title: Design, synthesis, and biological activities of a potent and selective alpha-melanotropin antagonist.
abstract: Based on structure-activity relationships of the potent alpha-MSH agonist, Ac-Nle4-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10-NH2, several analogs of the general formula Ac-Nle4-Asp5-Waa6-Xaa7-Yaa8-Zaa9-Lys10+ ++-NH2 were synthesized and tested on frog and lizard skin bioassays for their possible inhibitory actions against alpha-MSH on melanocyte stimulation. When Waa6 = Trp, Xaa7 = D-Phe, Yaa8 = Nle and Zaa = Trp, a highly potent alpha-MSH antagonist, Ac-Nle-Asp-Trp-D-Phe-Nle-Trp-Lys-NH2, with selectivity on the frog skin alpha-MSH receptor system (pA2 = 8.4) was obtained. However, several modifications in the amino acid sequence of the peptide resulted in a complete loss of antagonistic activity and a recovery of very weak agonistic action. The following changes in the amino acid sequence of the peptide were examined; His or D-Trp for Waa, L-Phe for Xaa, Arg, Ala or Pro for Yaa, and D-Trp for Zaa. All resulted in full agonists with no antagonistic activity. In addition, lactam cyclization between the Asp5 and Lys10 side chains in the antagonist gave a full agonist and a complete loss of antagonistic activity. Efforts to develop a rational approach for the design of selective alpha-MSH antagonists for the frog skin alpha-MSH receptor will be discussed.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson.
authors.forename: F
authors.initials: F
authors.lastname: al-Obeidi
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: M E
authors.initials: ME
authors.lastname: Hadley
authors.forename: T K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: A M
authors.initials: AM
authors.lastname: Castrucci
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D008116:Lizards; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011894:Rana pipiens; D011979:Receptors, Pituitary Hormone / Q000187:drug effects; D012867:Skin / Q000166:cytology / Q000378:metabolism; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000037:antagonists & inhibitors*
chemical_list: D008543:Melanins; D009842:Oligopeptides; D011979:Receptors, Pituitary Hormone; D000521:alpha-MSH; C029446:MSH receptor