title: Discovery and structure-activity relationships of novel alpha-melanocyte-stimulating hormone inhibitors.
abstract: Novel D-amino acid modified, hexapeptide inhibitors of alpha-melanocyte-stimulating hormone (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, alpha-MSH) are described. The discovery of the alpha-MSH inhibitory activity of a known somatotropin (growth hormone) secretagogue, H-His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 ([His1, Lys6-]GHRP, I), and its chemical similarity to the alpha-MSH6-11 sequence provided the impetus to investigate the structure-activity relationships of MSH-GHRP hybrid analogues. In this study we compared the melanotropic activity of a series of peptides of the generic formula H-His-Xaa-Yaa-Trp-D-Phe-Lys-NH2 (H-[Xaa7, Yaa8, D-Phe10] alpha-MSH6-11-NH2) on the R. pipiens (frog) and A. carolinensis (lizard) skin in vitro bioassays. In summary, D-Phe7-Ala8 substitution (II) in the heptapeptide template yielded an MSH-like agonist of moderately low potency (EC50 ca. 10(-6) M) relative to alpha-MSH; D-Ala7-Ala8 substitution (III) abolished agonist or antagonist activity. alpha-MSH inhibition was effected by MSH-GHRP analogues having D-Trp7-Ala8, D-Arg7-Ala8, D-Trp7-Arg8 or Phe7-Arg8 substitutions. The D-Trp7-Ala8 and Phe7-Arg8 modified derivatives (I and VI) selectively inhibited alpha-MSH on the R. pipiens assay (pA2 = 4.7 and 5.8, respectively), as they did not possess antagonist (or agonist) activities on the A. carolinensis assay. In contrast, the D-Arg7-Ala8 and D-Trp7-Arg8 modified derivatives (IV and V) inhibited alpha-MSH on both the R. pipiens and A. carolinensis assays (pA2 values ranging 5.0-6.0).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Upjohn Company, Kalamazoo, MI 49001.
authors.forename: T K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: D J
authors.initials: DJ
authors.lastname: Staples
authors.forename: A M
authors.initials: AM
authors.lastname: Castrucci
authors.forename: M E
authors.initials: ME
authors.lastname: Hadley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008116:Lizards; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011894:Rana pipiens; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D000521:alpha-MSH