Hybrid Cholecystokinin-A Antagonists Based on Molecular Modelling of Lorglumide and L-364,718

Article abstract of DOI:10.1021/jm00084a009

A series of novel nonpeptide cholecystokinin-A (CCK-A) antagonists have been synthesized.Designed on the basis of the structural homology between lorgumide 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 K_i 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.