Characterization of a new CCK antagonist, L364,718: In vitro and in vivo studies

In this study the authors 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. They used isolated rat pancreatic acini and incubated them with CCK-8 with or without various CCK receptor antagonists. L364,718, proglumide, and the proglumide derivative CR1409 each caused a progressive rightward shift in the CCK-8-dose-response curve without a change in maximal amylase secretion. 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. To verify that L364,718 is an effective receptor antagonists against the various molecular forms of CCK released endogenously in humans, postprandial plasma CCK was extracted and bioassayed using amylase release from isolated pancreatic acini. Thus L364,718 is the most potent, selective peripheral CCK receptor antagonist reported to data, and it is capable of antagonizing the stimulatory action of exogenously as well as endogenously released CCK to evoke amylase release from pancreatic acini