AJP - Gastrointestinal and Liver Physiology, Vol 249, Issue 2 214-G220, Copyright © 1985 by American Physiological Society
Proglumide analogues: potent cholecystokinin receptor antagonists
R. T. Jensen, R. B. Murphy, M. Trampota, L. H. Schneider, S. W. Jones, J. M. Howard and J. D. Gardner
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)
