Cholecystokinin-A Specific Antagonism of KSG-504 to Cholecystokinin Receptor Binding and Pancreatic Secretion in Mammals

Abstract

ABSTRACT-The effects of KSG-504 ((S)-arginium (R)-4-[-N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl) pentanoate monohydrate), a new cholecystokinin (CCK)-receptor antagonist, on 125I-CCK-8 binding to rat pancreatic, canine gallbladder and guinea pig cerebrocortical membranes and the pancreatic amylase release from isolated rat acini stimulated by several kinds of secretagogues, including CCK, were investigated. The 125I-CCK-8 saturation experiment showed that pancreatic, gallbladder and cerebrocortical CCK receptors had a single high affinity binding component with dissociation constants (Kd) of 0.18, 0.31 and 0.88 nM, respectively. The maximum numbers of specific binding sites (Bma,,) in these membranes were 1012, 52 and 20 fmol/mg protein, respectively. KSG-504 and CCK-8 displaced specific 125I -CCK-8 binding to CCK receptors in all membrane preparations in a competitive manner. The affinity of KSG-504 for pancreatic (K;=173 nM) and gallbladder (K;=283 nM) CCK receptors were > 3 orders of magnitude higher than its affinity for cerebrocortical CCK receptors. KSG-504 also inhibited 125I-gastrin-I binding to guinea pig gastric glands, but the IC50 value (18.2 pM) was apparently much higher. CCK-8-stimulated amylase release from isolated pancreatic acini of rats was antagonized by KSG-504 in a concentration-dependent manner. KSG-504 did not affect amylase release stimulated by secretagogues such as gastrin-releasing peptide, carbachol, vasoactive intestinal peptide and A23187. These results indicate that KSG-504 acts as a CCK-A-receptor-specific antagonist in the pancreas and gallbladder.