Development of Peptide 3D Structure Mimetics: Rational Design of Novel Peptoid Cholecystokinin Receptor Antagonists

J Med Chem. 2000 Sep 21;43(19):3505-17. doi: 10.1021/jm000937a.

Abstract

The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly(29)-Trp(30)-Met(31)-Asp(32)-Phe(33)-NH(2). Nevertheless, this congruence has not precluded using this structure to develop selective ligands for either CCK(1) or CCK(2) receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK(1) tripeptide antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pK(B) 6.8 +/- 0.3). Molecular modeling was used to identify the bioactive conformation of these CCK(1)-selective compounds and prompted the design of new peptoid structures. We aimed to maintain the conformation of the parent series by exploiting patterns of hydrogen-bonding and pi-stacking interactions present in the original molecule, rather than introducing additional covalent bonds. The prototype, N-(succinyl-D-Asp-2-phenylethylamido)-L-Trp-2-(2-naphthyl)ethylami de, was a potent and selective CCK(1) antagonist (pK(B) 7.2 +/- 0.3). Furthermore, the new series showed patterns of biological activity that mirrored those of the parent tripeptides. These compounds contain elements of both peptide primary and secondary structure and represent a novel approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK(1) antagonist with a conformation of CCK(30)(-)(33) that others have proposed to be responsible for its activity at the CCK(2) receptor. The results suggest that CCK(1) and CCK(2) receptors recognize enatiomeric dispositions of the Trp(30) indole, Asp(32) carboxylic acid, and C-terminal phenyl groups arrayed about a common backbone configuration. This "functional chirality" may underpin the mechanism by which these closely related receptor systems bind CCK(30)(-)(33) and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands.

MeSH terms

  • Animals
  • Binding, Competitive
  • Cerebral Cortex / metabolism
  • Cholecystokinin / chemistry
  • Gallbladder / drug effects
  • Gallbladder / physiology
  • Gastric Acid / metabolism
  • Guinea Pigs
  • In Vitro Techniques
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Mimicry
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacology
  • Pancreas / metabolism
  • Peptide Fragments / chemistry
  • Peptides / chemistry*
  • Peptoids
  • Rats
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Stereoisomerism

Substances

  • Ligands
  • N-(succinyl-Asp-2-phenylethylamido)-Trp-2-(2-naphthyl)ethylamide
  • Oligopeptides
  • Peptide Fragments
  • Peptides
  • Peptoids
  • Receptors, Cholecystokinin
  • Cholecystokinin