Cholecystokinin Antagonists: (R)-tryptophan-based Hybrid Antagonists of High Affinity and Selectivity for CCK-A Receptors

J Med Chem. 1991 Dec;34(12):3350-9. doi: 10.1021/jm00116a002.

Abstract

The intriguing structural similarities of glutamic acid based cholecystokinin (CCK) antagonists (A-64718 and A-65186) and the benzodiazepine CCK antagonist MK-329 (L-364,718) have been reported. Efforts to include the weak CCK antagonist benzotript into this construct utilizing a similar approach have resulted in a novel series of benzotript-based hybrid antagonists N alpha-(3'-quinolylcarbonyl)-(R)-tryptophan di-n-pentylamide (9, A-67396), N alpha-(4',8'-dihydroxy-2'-quinolylcarbonyl)-(R)-tryptophan di-n-pentylamide (23, A-70276), and N alpha-(3'-quinolylcarbonyl)-(R)-5'-hydroxytryptophan di-n-pentylamide (36, A-71134) which possess respectively binding affinities of 23, 21, and 11 nM for the pancreatic CCK-A receptor and which inhibit CCK8-induced amylase secretion. Compound 9 possesses a selectivity of greater than 500-fold for the pancreatic CCK-A receptor over the CCK-B receptor.

MeSH terms

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • Binding, Competitive
  • Cholecystokinin / antagonists & inhibitors*
  • Glutamates / chemical synthesis
  • Glutamates / pharmacology
  • Guinea Pigs
  • In Vitro Techniques
  • Receptors, Cholecystokinin / drug effects*
  • Receptors, Cholecystokinin / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tryptophan / analogs & derivatives*
  • Tryptophan / chemical synthesis
  • Tryptophan / pharmacology

Substances

  • Benzamides
  • Glutamates
  • Receptors, Cholecystokinin
  • Tryptophan
  • Cholecystokinin
  • benzotript