CHOLECYSTOKININ-A SPECIFIC ANTAGONISM OF KSG-504 TO CHOLECYSTOKININ RECEPTOR-BINDING AND PANCREATIC-SECRETION IN MAMMALS

The effects of KSG-504 (((S)arginium ypropyl)-N-pentylcarbamoyl]-5-(2- naphthylsulfonyl) pentanoate monohydrate), a new cholecystokinin (CCK) -receptor antagonist, on I-125-CCK-8 binding to rat pancreatic, canine gallbladder and guinea pig cerebrocortical membranes and the pancreat ic amylase release from isolated rat acini stimulated by several kinds of secretagogues, including CCK, were investigated. The I-125-CCK-8 s aturation experiment showed that pancreatic, gallbladder and cerebroco rtical CCK receptors had a single high affinity binding component with dissociation constants (K-d) of 0.18, 0.31 and 0.88 nM, respectively. The maximum numbers of specific binding sites (B-max) in these membra nes were 1012, 52 and 20 fmol/mg protein, respectively. KSG-504 and CC K-8 displaced specific I-125-CCK-8 binding to CCK receptors in all mem brane preparations in a competitive manner. The affinity of KSG-504 fo r pancreatic (K-i=173 nM) and gallbladder (K-i=283 nM) CCK receptors w ere >3 orders of magnitude higher than its affinity for cerebrocortica l CCK receptors. KSG-504 also inhibited I-125-gastrin-I binding to gui nea pig gastric glands, but the IC50 value (18.2 mu M) was apparently much higher. CCK-8-stimulated amylase release from isolated pancreatic acini of rats was antagonized by KSG-504 ina concentration-dependent manner. KSG-504 did not affect amylase release stimulated by secretago gues such as gastrin-releasing peptide, carbachol, vasoactive intestin al peptide and A23187. These results indicate that KSG-504 acts as a C CK-A-receptor-specific antagonist in the pancreas and gallbladder.