Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists

J Med Chem. 1988 Dec;31(12):2235-46. doi: 10.1021/jm00120a002.


3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzodiazepines / chemical synthesis*
  • Benzodiazepines / metabolism
  • Chemical Phenomena
  • Chemistry
  • Cholecystokinin / antagonists & inhibitors*
  • Drug Design*
  • Mice
  • Receptors, Cholecystokinin / metabolism
  • Receptors, GABA-A / metabolism
  • Structure-Activity Relationship


  • Receptors, Cholecystokinin
  • Receptors, GABA-A
  • Benzodiazepines
  • Cholecystokinin