HYBRID CHOLECYSTOKININ-A ANTAGONISTS BASED ON MOLECULAR MODELING OF LORGLUMIDE AND L-364,718

A series of novel nonpeptide cholecystokinin-A (CCK-A) antagonists hav e been synthesized. Designed on the basis of the structural homology b etween lorglumide and L-364,718, as investigated with molecular modeli ng, 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 [H-3]-(+/-)-L-364,718 and [H-3]-CCK-8(S) to rat pancreas and guinea pig brain membranes, respectively. All compounds proved to be selecti ve for the (peripheral) CCK-A receptor, the most potent analogue, 6, h aving a K(i) value of 90 nM. The structure-activity profile of the ser ies of hybrid compounds relates closest to that of the N-acylglutamic acid derived antagonists.