title: Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions.
abstract: The melanocortin system is involved in the regulation of several diverse physiological pathways, including energy homeostasis. Several synthetic peptide analogs have been designed, synthesized, and pharmacologically characterized at the mouse melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119. Analogs containing DNal(2') at position 7 resulted in partial agonist and antagonistic activities at the mMC3R while possessing full antagonistic activities at the mMC4R. Recently, the melanocortin-5 receptor (MC5R) has been demonstrated to have a role in the regulation of exocrine gland function. This study has characterized the following analogs of SHU9119 that possess antagonist activity at the MC5R: Ac-Nle-c[Asp-(1-Me)His(6)-DNal(2')(7)-Arg-Trp-Lys]-NH(2), pA(2) = 7. 1; Ac-Nle-c[Asp-(1-Me)His(6)-DNal(2')(7)-Arg-Nal(2')(9)-Lys]-NH(2), pA(2) = 7.2; and Ac-Nle-c[Asp-Trp(6)-DNal(2')(7)-Arg-Nal(2')(9)-Lys]-NH(2), pA(2) = 6. 6.
authors.affiliation: Vollum Institute, Oregon Health Sciences University, Portland, OR 97201, USA. Carrie@cop.ufl.edu
authors.forename: C
authors.initials: C
authors.lastname: Haskell-Luevano
authors.forename: S
authors.initials: S
authors.lastname: Lim
authors.forename: W
authors.initials: W
authors.lastname: Yuan
authors.forename: R D
authors.initials: RD
authors.lastname: Cone
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000145:classification; D044101:Receptors, Melanocortin; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C470053:Mc3r protein, mouse; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; C086971:melanocortin 5 receptor; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones