Proglumide analogues: potent cholecystokinin receptor antagonists.
Proglumide [N-(benzoyl)-L-glutamic acid-1-di-n-propylamide] is a specific cholecystokinin receptor antagonist. In the present study we synthesized various analogues of proglumide and used pancreatic acini from guinea pig pancreas to examine the abilities of these analogues to function as cholecystokinin receptor antagonists. Each analogue inhibited cholecystokinin octapeptide-stimulated amylase secretion but did not stimulate amylase secretion when present alone. There was a close correlation between the ability of a particular analogue to inhibit the action of cholecystokinin on acinar cell function and its ability to inhibit binding of 125I-cholecystokinin. Structure-function studies demonstrated that neither the dipropylamide nor the benzoyl moieties are essential for inhibiting the action of cholecystokinin but that both groups are important in determining the inhibitory potency. Replacing the dipropylamide group with a hydroxyl group caused a 13-fold decrease in potency. Replacing the benzoyl moiety by an acetyl group caused a 30- to 40-fold decrease in inhibitory potency, whereas replacing the benzoyl moiety by a p-chlorophenoxyacetyl or phenoxyacetyl moiety caused a 75-fold increase in potency. Replacing both the dipropylamide moiety with a hydroxyl group and the benzoyl moiety with a phenoxyacetyl group resulted in a 5-fold decrease in inhibitory potency. Inhibition of cholecystokinin-stimulated amylase release by both the phenoxyacetyl and p-chlorophenoxyacetyl analogues was competitive in nature, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
R T
RT
Jensen
R B
RB
Murphy
M
M
Trampota
L H
LH
Schneider
S W
SW
Jones
J M
JM
Howard
J D
JD
Gardner
D000681:Amylases / Q000378:metabolism; D000818:Animals; D005973:Glutamine / Q000031:analogs & derivatives*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D011377:Proglumide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011949:Receptors, Cholecystokinin; D012844:Sincalide / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D011956:Receptors, Cell Surface; D011949:Receptors, Cholecystokinin; D005973:Glutamine; D000681:Amylases; D011377:Proglumide; D012844:Sincalide