Development of potent and selective CCK-A receptor agonists from Boc-CCK-4: tetrapeptides containing Lys(N epsilon)-amide residues

J Med Chem. 1992 May 29;35(11):2007-14. doi: 10.1021/jm00089a010.


A series of Boc-CCK-4 derivatives represented by the general structure Boc-Trp-Lys(N epsilon-COR)-Asp-Phe-NH2, where R is an aromatic, heterocyclic, or aliphatic group, are potent and selective CCK-A receptor agonists. These amide-bearing compounds complement the previously described urea-based tetrapeptides (Shiosaki et al. J. Med. Chem. 1991, 34, 2837-2842); structure-activity studies revealed parallel as well as divergent trends between these two series. A significant correlation was observed between pancreatic binding affinity and the resonance constant R of the phenyl substituent in one particular series of derivatives. Sulfation of phenolic amides appended onto the epsilon-amino group of the lysine did not affect affinity for the CCK-A receptor in contrast to the 500-fold increase in binding potency observed upon sulfation of CCK-8, suggesting that the lysine appendage and the sulfated tyrosine in CCK-8, both key structural elements that impart high affinity for the CCK-A receptor, are interacting differently with the receptor. The amide-bearing tetrapeptides are full agonists relative to CCK-8 in stimulating pancreatic amylase release while being partial agonists in eliciting phosphoinositide (PI) hydrolysis. Both effects were blocked by selective CCK-A receptor antagonists.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Amylases / metabolism
  • Animals
  • Formic Acid Esters / chemistry*
  • Formic Acid Esters / metabolism
  • Guinea Pigs
  • Molecular Sequence Data
  • Molecular Structure
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Receptors, Cholecystokinin / metabolism*
  • Sincalide / chemistry
  • Sincalide / metabolism
  • Sincalide / pharmacology
  • Structure-Activity Relationship


  • Formic Acid Esters
  • Oligopeptides
  • Receptors, Cholecystokinin
  • t-butyloxycarbonyl group
  • Amylases
  • Sincalide