AJP - Gastrointestinal and Liver Physiology, Vol 251, Issue 6 839-G846, Copyright © 1986 by American Physiological Society
Structural features of various proglumide-related cholecystokinin receptor antagonists
R. T. Jensen, Z. C. Zhou, R. B. Murphy, S. W. Jones, I. Setnikar, L. A. Rovati and J. D. Gardner
Thirteen proglumide derivatives that varied in the length of the di-n-alkyl
group and in the substitutions on the benzoyl moiety were tested for their
ability to interact with guinea pig pancreatic cholecystokinin (CCK)
receptors. Each derivative was more potent than proglumide. There was a
close correlation between their abilities to inhibit CCK-stimulated amylase
release and to inhibit binding of 125I-CCK. For the di-n-alkyl derivatives
the relative potency was n-pentyl greater than n-hexyl greater than n-butyl
greater than n-propyl. For the benzoyl moiety, adding two
electron-withdrawing groups increased potency more than adding a single
electron-withdrawing group or adding electron-donating groups. The
3,4-dichloro-di-n-pentyl derivative of proglumide was 1,300 times more
potent than proglumide, and its action was specific, competitive, and it
functioned as a CCK receptor antagonist in rat, mouse, and guinea pig
pancreas. For all proglumide derivatives there was a good correlation (r =
0.84, P less than 0.001) between their abilities to inhibit CCK-stimulated
amylase release and that previously reported for their abilities to inhibit
CCK-induced gallbladder contraction. However, certain proglumide
derivatives had a much higher affinity for the pancreatic CCK receptor than
for the CCK receptor mediating gallbladder contraction. For other
proglumide derivatives the pattern was reversed. These results demonstrate
that both the di-n-alkyl group and the substitution on the benzoyl moiety
of proglumide are equally important determinants of affinity and that
derivatives such as the di-n-pentyl 3,4-dichloro analogue can be produced
that are 1,300 times more potent than proglumide.(ABSTRACT TRUNCATED AT 250
WORDS)
