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

Journal Article · Thu Sep 01 04:00:00 EDT 1988 · American Journal of Physiology; (USA)

OSTI ID:6809001

Louie, D S; Liang, Jiang Ping; Owyang, Chung ^[1]

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1. Univ. of Michigan Medical Center, Ann Arbor (USA)

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 {sup 125}I-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.

• OSTI ID: 6809001
• Journal Information: American Journal of Physiology; (USA), Journal Name: American Journal of Physiology; (USA) Vol. 255:3; ISSN 0002-9513; ISSN AJPHA
• Country of Publication: United States
• Language: English

Related Subjects

551001* -- Physiological Systems-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMYLASE
ANIMALS
AROMATICS
AZAARENES
AZOLES
BETA DECAY RADIOISOTOPES
BODY
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
DAYS LIVING RADIOISOTOPES
DERIVATIZATION
DIGESTIVE SYSTEM
DOSE-RESPONSE RELATIONSHIPS
ELECTRON CAPTURE RADIOISOTOPES
ENDOCRINE GLANDS
ENZYMES
GASTROINTESTINAL TRACT
GLANDS
GLYCOSYL HYDROLASES
HETEROCYCLIC COMPOUNDS
HYDROLASES
IN VIVO
INDOLES
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
KININS
MAMMALS
MAN
MEMBRANE PROTEINS
MONOCARBOXYLIC ACIDS
MUSCLES
NUCLEI
O-GLYCOSYL HYDROLASES
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PANCREAS
PEPTIDES
POLYPEPTIDES
PRIMATES
PROTEINS
PYRROLES
RADIOISOTOPES
RADIORECEPTOR ASSAY
RATS
RECEPTORS
RODENTS
SECRETION
TRACER TECHNIQUES
VALERIC ACID
VERTEBRATES