AJP - Gastrointestinal and Liver Physiology, Vol 255, Issue 3 261-G266, Copyright © 1988 by American Physiological Society
Characterization of a new CCK antagonist, L364,718: in vitro and in vivo studies
D. S. Louie, J. P. Liang and C. Owyang
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0362.
In this study we examined a novel, orally effective, nonpeptidal
cholecystokinin (CCK) antagonist,
3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)
-1H-indole-2-carboxamide (L364,718) on CCK-induced amylase release. We used
isolated rat pancreatic acini and incubated them with CCK-8 with or without
various CCK receptor antagonists. L364,718 (3-100 nM), proglumide (1-10
mM), and the proglumide derivative CR1409 (1-30 microM) each caused a
progressive rightward shift in the CCK-8 dose-response curve without a
change in maximal amylase secretion. Plotting the data according to the
method of Schild indicated competitive inhibition. The Kis for L364,718,
CR1409, and proglumide were 0.25 nM, 0.15 microM, and 0.5 mM, respectively.
Thus L364,718 was 600-fold more potent than CR1409 and 2,000,000-fold more
potent than proglumide in inhibiting CCK-8-induced amylase release.
Inhibition of 125I-Bolton-Hunter-CCK-8 binding to acini by these receptor
antagonists had a similar rank potency. L364,718 was tested against other
pancreatic exocrine secretagogues and was effective against agonists that
only act through the CCK receptor. In rats, diversion of pancreatic juice
from the duodenum stimulated pancreatic amylase output and elevated plasma
CCK levels. The stimulated amylase secretion was blocked by intravenous
administration of L364,718. Furthermore, extracted plasma CCK from rats
with diversion of pancreatic juice from the duodenum stimulated amylase
release from pancreatic acini, and this stimulation was blocked by addition
of L364,718.(ABSTRACT TRUNCATED AT 250 WORDS)
