PHARMACOLOGICAL PROFILE OF KSG-504, A NEW CHOLECYSTOKININ-A-RECEPTOR ANTAGONIST

Pharmacological effects of KSG-504, a newly synthesized compound, on t he response induced by exogenous CCK-8 were investigated. KSG-504 inhi bited I-125-CCK-8 binding to both rat pancreas and cerebral cortex wit h 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 e stimated as 400. In the isolated pancreatic acini of rats, KSG-504 cau sed a parallel rightward shift of the concentration-response curve for CCK-8-stimulated amylase release with no change in its maximal respon se, indicating a competitive antagonism of the drug for the CCK-A rece ptor (Schild plot analysis; slope = 0.927, pA2 = 6.9). In addition, KS G-504 produced a significant inhibition of CCK-8-induced pancreatic am ylase secretion when administered intravenously or intraduodenally to rats (ED50: 52 mug/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-stimu lated pancreatic secretion and gallbladder contraction in dogs with ED 50 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 conce ntration-dependent manner (IC50 = 3.0 x 10(-6) M). These results demon strate that KSG-504 is a competitive and selective CCK-A-receptor anta gonist that is effective in vivo after oral administration.