Analogs of Ac-CCK-7 Incorporating Dipeptide Mimics in Place of Met28-Gly29

J Med Chem. 1992 Oct 16;35(21):3774-83. doi: 10.1021/jm00099a005.

Abstract

A series of analogs of Ac-CCK-7 [Ac-Tyr(SO3H)-Met28-Gly29-Trp-Met-Asp- Phe-NH2, (1)] were prepared in which the Met28-Gly29 dipeptide was replaced by omega-aminoalkanoic acids. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK-A and CCK-B receptors, respectively, and for anorectic activity after intraperitoneal administration to rats. The analog incorporating 4-aminobutanoic acid (5) was only 8 times less potent than 1 in the pancreatic binding assay, was more potent in the striatal binding assay, and was more potent than 1 in reducing food intake in rats. Using a bioactive cyclic analog of Ac-CCK-7 as a template, several rigid spacers were designed and tested as substitutes for the Met28-Gly29 dipeptide. The analogs incorporating 3-aminobenzoic acid (20) and (1S)-trans-2-aminocyclopentanecarboxylic acid (26) proved highly effective in the binding assays and as anorectic agents. We hypothesize that for stimulation of CCK-A receptors, the main function of the N-terminal tripeptide of Ac-CCK-7 is to orient the tyrosine sulfate with respect to Trp30 and that the bioactive arrangement of these elements lies among those which are readily available to both 20 and 26. NOESY and distance-constrained molecular dynamics experiments carried out on 20 and 26 identified conformations in which the relative orientation of the tyrosine hydroxide and the alpha-carbon atom of tryptophan were similar, providing the basis for further drug design efforts.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cattle
  • Cholecystokinin / analogs & derivatives*
  • Cholecystokinin / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dipeptides / chemistry
  • Feeding Behavior / drug effects
  • Glycine / chemistry
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Methionine / chemistry
  • Molecular Sequence Data
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Protein Conformation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cholecystokinin / drug effects
  • Receptors, Cholecystokinin / metabolism

Substances

  • Dipeptides
  • Receptors, Cholecystokinin
  • Cholecystokinin
  • Methionine
  • Glycine