Open AccessPharmacological Profile of KSG-504, a New Cholecystokinin-A-Receptor Antagonist
Author(s) -
Yoshinobu Yamazaki,
Masuo Akahane,
Mamoru Kobayashi,
Masato Kitazawa,
Yoshikazu Kurashina,
Kinji Iizuka
Publication year - 1993
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.63.219
Subject(s) - cholecystokinin , chemistry , cholecystokinin receptor , medicine , endocrinology , ed50 , schild regression , receptor antagonist , receptor , antagonist , biology , biochemistry
Pharmacological effects of KSG-504, a newly synthetized compound, on the response induced by exogenous CCK-8 were investigated. KSG-504 inhibited 125I-CCK-8 binding to both rat pancreas and cerebral cortex with IC50 values of 2.0 x 10(-7) M and 8.0 x 10(-5) M, respectively. The selectivity ratio of KSG-504 for pancreatic CCK receptor (CCK-A) was estimated as 400. In the isolated pancreatic acini of rats, KSG-504 caused a parallel rightward shift of the concentration-response curve for CCK-8-stimulated amylase release with no change in its maximal response, indicating a competitive antagonism of the drug for the CCK-A receptor (Schild plot analysis; slope = 0.927, pA2 = 6.9). In addition, KSG-504 produced a significant inhibition of CCK-8-induced pancreatic amylase secretion when administered intravenously or intraduodenally to rats (ED50: 52 micrograms/kg/min by the i.v. route and 12.1 mg/kg by the i.d. route). KSG-504 had equipotent inhibitory effects on both CCK-8-stimulated pancreatic secretion and gallbladder contraction in dogs with ED50 values of 0.98 and 0.84 mg/kg, respectively. KSG-504 also inhibited the CCK-8-induced contraction of isolated guinea pig ileum in a concentration-dependent manner (IC50 = 3.0 x 10(-6) M). These results demonstrate that KSG-504 is a competitive and selective CCK-A-receptor antagonist that is effective in vivo after oral administration.