Pharmacological Profile of KSG-504, a New Cholecystokinin-A-Receptor Antagonist.

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Pharmacological effects of KSG-504, a newly synthesized 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 2.0×10-7 M and 8.0×10-5 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 μg/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=3.0×10-6 M). These results demonstrate that KSG-504 is a competitive and selective CCK-A-receptor antagonist that is effective in vivo after oral administration.
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