Gastrin releasing peptide antagonists with improved potency and stability

J Med Chem. 1991 Jul;34(7):2102-7. doi: 10.1021/jm00111a027.


Gastrin releasing peptide (GRP) is a 27 amino acid peptide hormone which is homologous to the amphibian peptide bombesin. Two series of novel GRP antagonists were developed by C-terminal modification of N-acetyl-GRP-20-27 amide. Peptide derivatives within each series resist enzymatic degradation in serum and exhibit strong affinity for the GRP receptor. The first series of compounds replaces the Leu26-Met27 region of GRP with an alkyl ether N-acetyl-GRP-20-25-NH-[(S)-1-ethoxy-4-methyl-2-pentane], specifically blocked radiolabeled GRP binding with an IC50 of 6 nM. In the second series of antagonists the oxygen of the ether moiety is replaced with a methylene group, resulting in GRP antagonists which are equipotent to native GRP in receptor binding assays (IC50 = 2 nM) and are also resistant to proteolytic degradation in vitro. All of the C-terminally modified peptides tested blocked GRP-stimulated mitogenesis in Swiss 3T3 mouse fibroblasts. Representative compounds also blocked GRP-induced elevation of [Ca2+]i in human SCLC cells, and inhibited GRP-independent release of gastrin in vivo.

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Female
  • Gastrin-Releasing Peptide
  • Gastrins / blood
  • Humans
  • Mice
  • Peptides / antagonists & inhibitors*
  • Peptides / chemical synthesis*
  • Peptides / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Stereoisomerism
  • Structure-Activity Relationship


  • Gastrins
  • Peptides
  • Gastrin-Releasing Peptide