5-(tryptophylamino)-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based cholecystokinin receptor antagonists: reversal of CCK1 receptor subtype selectivity toward CCK2 receptors

J Med Chem. 2004 Oct 7;47(21):5318-29. doi: 10.1021/jm0498755.


With the aim of reversing selectivity or antagonist/agonist functionality in the 5-(tryptophylamino)-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-derived potent and highly selective CCK(1) antagonists, a series of 4-benzyl and 4-methyl derivatives have been synthesized. Whereas the introduction of the benzyl group led, in all cases, to complete loss of the binding affinity, the incorporation of the methyl group gave a different result depending on the stereochemistry of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold. Thus, the introduction of the methyl group into the (4aS,5R)-diastereoisomers, giving a (4S)-configuration, produced a 3-fold increase in the CCK(1) binding potency and selectivity. However, the same structural manipulation in the opposite (4aR,5S)-stereochemistry, leading to a (4R,4aR,5S)-configuration, produced reversal of the selectivity for CCK(1) to the CCK(2) receptors. The replacement of the Boc group at the tryptophan moiety by a 2-adamantyloxycarbonyl group also contributed to that reversal. The resulting compounds displayed moderate CCK(2) antagonist activity in rat and human receptors, and a very small partial agonist effect on the production of inositol phosphate in COS-7 cells transfected with the wild-type human CCK(2) receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amylases / metabolism
  • Animals
  • Binding, Competitive
  • COS Cells
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Humans
  • In Vitro Techniques
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, Cholecystokinin B / antagonists & inhibitors*
  • Receptors, CCR1
  • Receptors, Chemokine / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship


  • CCR1 protein, human
  • Ccr1 protein, rat
  • Pyridines
  • Pyrimidines
  • Receptor, Cholecystokinin B
  • Receptors, CCR1
  • Receptors, Chemokine
  • Amylases