Boc-CCK-4 Derivatives Containing Side-Chain Ureas as Potent and Selective CCK-a Receptor Agonists

J Med Chem. 1991 Sep;34(9):2837-42. doi: 10.1021/jm00113a023.

Abstract

Novel Boc-CCK-4 derivatives were communicated recently as having high potency and selectivity for the CCK-A receptor (Shiosaki et al. J. Med. Chem. 1990, 33, 2950-2952). While Boc-CCK-4 binds selectively to the CCK-B receptor, replacement of the methionine with an N epsilon-substituted lysine dramatically reversed receptor selectivity, leading to the development of this novel series of tetrapeptides. A detailed structure-activity analysis of a series of urea-substituted tetrapeptides, represented by the general structure Boc-Trp-Lys(N epsilon-CO-NHR)-Asp-Phe-NH2, revealed that a number of substituted phenyl, naphthyl, and aliphatic urea residues in the lysine side chain yielded potent and selective CCK-A ligands. These tetrapeptides elicit full agonist responses in stimulating pancreatic amylase release that are effectively blocked by a selective CCK-A receptor antagonist. Conversion of the urea to a thiourea significantly reduced CCK-A binding potency as did replacement of the lysine with the homologous ornithine or homolysine. Tetrapeptides that were partial agonists (less than 80% efficacy) in phosphoinositide (PI) hydrolysis relative to CCK-8 did not exhibit high-dose inhibition of amylase secretion in guinea pig acini.

MeSH terms

  • Amino Acid Sequence
  • Amylases / metabolism
  • Animals
  • Guinea Pigs
  • Hydrolysis
  • Molecular Sequence Data
  • Pancreas / drug effects
  • Pancreas / enzymology
  • Phosphatidylinositols / metabolism
  • Receptors, Cholecystokinin / drug effects*
  • Tetragastrin / analogs & derivatives*
  • Tetragastrin / chemistry
  • Tetragastrin / pharmacology
  • Urea / chemistry*

Substances

  • Phosphatidylinositols
  • Receptors, Cholecystokinin
  • Tetragastrin
  • butyloxycarbonyl-tryptophyl-methionyl-aspartyl-phenylalaninamide
  • Urea
  • Amylases