Hybrid cholecystokinin-A Antagonists Based on Molecular Modeling of Lorglumide and L-364,718

J Med Chem. 1992 Mar 20;35(6):1042-9. doi: 10.1021/jm00084a009.

Abstract

A series of novel nonpeptide cholecystokinin-A (CCK-A) antagonists have been synthesized. Designed on the basis of the structural homology between lorglumide and L-364,718, as investigated with molecular modeling, these compounds constitute a link between the N-acylglutamic acid and 3-amino-5-phenyl-1,4-benzodiazepin-2-one derived antagonists. The prepared compounds were tested in vitro as antagonists of the binding of [3H]-(+/-)-L-364,718 and [3H]-CCK-8(S) to rat pancreas and guinea pig brain membranes, respectively. All compounds proved to be selective for the (peripheral) CCK-A receptor, the most potent analogue, 6, having a Ki value of 90 nM. The structure-activity profile of the series of hybrid compounds relates closest to that of the N-acylglutamic acid derived antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodiazepinones / chemical synthesis*
  • Benzodiazepinones / chemistry
  • Benzodiazepinones / metabolism*
  • Benzodiazepinones / pharmacology
  • Cholecystokinin / antagonists & inhibitors*
  • Computer Simulation
  • Devazepide
  • Glutamates / chemical synthesis*
  • Glutamates / chemistry
  • Glutamates / pharmacology
  • Guinea Pigs
  • Male
  • Models, Molecular
  • Proglumide / analogs & derivatives*
  • Proglumide / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, Cholecystokinin / drug effects
  • Receptors, Cholecystokinin / metabolism
  • Structure-Activity Relationship

Substances

  • Benzodiazepinones
  • Glutamates
  • Receptors, Cholecystokinin
  • Cholecystokinin
  • Proglumide
  • Devazepide
  • lorglumide