Hybrid cholecystokinin-A antagonists based on molecular modeling of lorglumide and L-364,718.
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.
van der Bent
A
A
Division of Medicinal Chemistry, Center for Bio-Pharmaceutical Sciences, Leiden, The Netherlands.
Blommaert
A G
AG
Melman
C T
CT
IJzerman
A P
AP
van Wijngaarden
I
I
Soudijn
W
W
D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D020109:Devazepide; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D011377:Proglumide / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D001570:Benzodiazepinones; D005971:Glutamates; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; D011377:Proglumide; D020109:Devazepide; C048181:lorglumide