Characterization of the binding of (3H)-(+/-)-L-364,718: a new potent, nonpeptide cholecystokinin antagonist radioligand selective for peripheral receptors

Journal Article · Mon Sep 01 04:00:00 EDT 1986 · Mol. Pharmacol.; (United States)

OSTI ID:5009244

Chang, R S; Lotti, V J; Chen, T B; Kunkel, K A

(3H)-(+/-)-L-364,718 a new, potent and selective nonpeptide peripheral cholecystokinin (CCK) antagonist bound saturably and reversibly to rat pancreatic membranes. The radioligand recognized a single class of binding sites with a high affinity (Kd = 0.23 nM). The binding of (/sup 3/H)-(+/-)-L-364,718 was stereospecific in that the more biologically active (-)-enantiomer demonstrated greater potency than the (+)-enantiomer. The rank order of potency of various CCK agonists and antagonists in displacing (/sup 3/H)-(+/-)-L-364,718 correlated with their ability to displace (/sup 125/I)CCK-8 and their known pharmacological activities in peripheral tissues. However, the absolute potencies of agonists were greater in displacing (/sup 125/I)CCK-8 than (/sup 3/H)-(+/-)-L-364,718. As described for other physiologically relevant receptor systems, the potency for displacement of (/sup 3/H)-(+/-)-L-364,718 binding by CCK agonists, but not antagonists, was reduced by guanosine 5'-(beta, gamma-imido)triphosphate and NaCl and enhanced by MgCl/sub 2/. (/sup 3/H)-(+/-)-L-364,718 also demonstrated specific binding to bovine gall bladder tissue but not guinea pig brain or gastric glands, consistent with its selectivity as a peripheral CCK antagonist. (/sup 3/H)-(+/-)-L-364,718 binding to pancreatic membranes was not affected by various pharmacological agents known to interact with other common peptide and nonpeptide receptor systems. These data indicate that (/sup 3/H)-(+/-)-L-364,718 represents a new potent nonpeptide antagonist radioligand for the study of peripheral CCK receptors which may allow differentiation of agonist and antagonist interactions.

• Research Organization: Merck Sharp and Dohme Research Labs., West Point, PA
• OSTI ID: 5009244
• Journal Information: Mol. Pharmacol.; (United States), Journal Name: Mol. Pharmacol.; (United States) Vol. 3; ISSN MOPMA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BIOCHEMICAL REACTION KINETICS
BODY
CELL CONSTITUENTS
CELL MEMBRANES
COMPETITION
DIGESTIVE SYSTEM
ENDOCRINE GLANDS
GLANDS
IN VITRO
ISOTOPE APPLICATIONS
KINETICS
KININS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
MEMBRANES
ORGANIC COMPOUNDS
ORGANS
PANCREAS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIORECEPTOR ASSAY
RATS
REACTION KINETICS
RECEPTORS
RODENTS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES