Boc-Trp-Orn(Z)-Asp-NH2 and Derivatives: A New Family of CCK Antagonists

J Med Chem. 1990 Dec;33(12):3199-204. doi: 10.1021/jm00174a016.

Abstract

The respective roles of the benzyloxycarbonyl group (Z) and of the N-terminal tripeptide moiety in the antagonist properties of the cholecystokinin CCK8 analogue Boc-[Nle28,Orn(Z)31]CCK27-33 (Marseigne et al. J. Med. Chem. 1988, 31, 966.) were studied with the following derivatives: Boc-[Nle28,Orn(X)31]CCK27-33, Boc[Nle28,Orn(X)31]CCK27-32, Boc-[Orn(X)31]CCK30-33, and Boc-[Orn(X)31]CCK30-32 (X = Z, Boc, H). These derivatives, the synthesis of eight of which is reported here, were tested for their abilities to inhibit the binding of [3H]pCCK8 to guinea pig pancreatic and brain membranes and for their potencies in stimulating amylase release from guinea pig pancreatic acini. None of the Z derivatives produced amylase secretion, but they competitively antagonized the stimulation induced by CCK8. The deletion of the N-terminal tripeptide and/or Phe-NH2(33) residue did not play a key role in the recognition of peripheral receptors and in the activity of these peptides, whereas replacement of the Z group by a Boc group slightly decreased the affinities of the compounds for both pancreatic and brain binding sites and their potencies as peripheral antagonists. Moreover, the tetrapeptide Boc-Trp-Orn(Boc)-Asp-Phe-NH2 behaved as a partial agonist and analogues in which the Z or Boc groups on the ornithine residue were removed were full agonists. Interestingly, the short peptide derivative Boc-Trp-Orn(Z)-Asp-NH2 displayed the same affinity (KI = 2.0 +/- 0.2 x 10(-7] and the same antagonist activity (pA2 = 6.63) as its parent compound Boc-[Nle28,Orn(Z)31]CCK27-33. This tripeptide could be an interesting tool for studying the structural relationships between peptide and non-peptide CCK antagonists.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amylases / metabolism
  • Animals
  • Binding, Competitive
  • Biological Assay
  • Brain / drug effects
  • Brain / metabolism
  • Cell Membrane / metabolism
  • Chemical Phenomena
  • Chemistry
  • Cholecystokinin / antagonists & inhibitors*
  • Guinea Pigs
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis
  • Oligopeptides / pharmacology*
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Receptors, Cholecystokinin / metabolism
  • Sincalide / analogs & derivatives
  • Sincalide / metabolism
  • Structure-Activity Relationship

Substances

  • Oligopeptides
  • Receptors, Cholecystokinin
  • tert-butyloxycarbonyl-tryptophyl-benzyloxycarbonyl-ornithyl-aspartamide
  • Cholecystokinin
  • Amylases
  • Sincalide