Structure-activity relationship of linear peptide Bu-His-DPhe-Arg-Trp-Gly-NH(2) at the human melanocortin-1 and -4 receptors: histidine substitution

Bioorg Med Chem Lett. 2003 Jan 6;13(1):133-7. doi: 10.1016/s0960-894x(02)00830-2.

Abstract

Systematic substitution of His(6) residue using non-selective hMC4R pentapeptide agonist (Bu-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2)) as the template led to the identification of Bu-Atc(6)(2-aminotetraline-2-carboxylic acid)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which showed moderate selectivity towards hMC4R over hMC1R. Further SAR studies resulted in the discovery of Penta-5-BrAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) and Penta-5-Me(2)NAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which are potent hMC4R agonists and are inactive in hMC1R, hMC3R and hMC5R agonist assays.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Cyclic AMP / biosynthesis
  • Histidine
  • Humans
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Protein Binding
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin / agonists*
  • Receptors, Corticotropin / metabolism
  • Receptors, Melanocortin
  • Structure-Activity Relationship

Substances

  • Bu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2)
  • Oligopeptides
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin
  • Receptors, Melanocortin
  • Histidine
  • Cyclic AMP