title: Pharmacological profile of KSG-504, a new cholecystokinin-A-receptor antagonist.
abstract: 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.
authors.affiliation: Creative Products Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: M
authors.initials: M
authors.lastname: Akahane
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Kitazawa
authors.forename: Y
authors.initials: Y
authors.lastname: Kurashina
authors.forename: K
authors.initials: K
authors.lastname: Iizuka
mesh_terms: D000681:Amylases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004285:Dogs; D005260:Female; D005704:Gallbladder / Q000187:drug effects*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology; D010421:Pentanoic Acids / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000494:pharmacology; D013045:Species Specificity
chemical_list: D009281:Naphthalenes; D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; C085253:KSG 504; D000681:Amylases; D012844:Sincalide