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

Abstract

ABSTRACT-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 x 10' 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 signifi cant inhibition of CCK-8-induced pancreatic amylase secretion when administered intravenously or intra duodenally to rats (ED50: 52 pg/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 con traction 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.

Cholecystokinin-A Specific Antagonism of KSG-504 to Cholecystokinin Receptor Binding and Pancreatic Secretion in Mammals

“…KSG-504 had no inhibitory effects on the amylase release stimulated by other secretagogues that interact with different receptors or by a secretagogue that acts on a post-receptor mechanism. We have previously reported that the antagonism of KSG-504 against the pancreatic CCK-A receptors is competitive (17). Thus, the results of the current study clearly demonstrated that the antagonistic action of KSG-504 on the amylase release from the pancreatic acini was selective for CCK-A receptors.…”

“…Recently, KSG-504 ((S)-arginium (R)-4-[-N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl) pentanoate monohydrate), a new non-peptide CCK-receptor antagonist, has been synthesized by Kissei Pharmaceutical Co., Ltd. We have clearly demonstrated that KSG-504 is highly specific for pancreatic CCK-A receptors and inhibits pancreatic exocrine secretion stimulated by CCK-8 (17). However, there have been no studies on the interaction of KSG-504 with gallbladder CCK or gastrin-type receptors.…”

Cholecystokinin antagonists: Pharmacological and therapeutic potential

“…118 On the other hand, the diasteroisomeric dipeptoids substituted at position 1 of the phenyl-ethylamine moiety 61-64 (Table XI) have proved the stereochemical preference for each receptor subtype. 219 Thus, the stereoisomer 61 (PD-135,666) was a potent and selective CCK 2 antagonist in the electrophysiological test on the rat ventromedial nucleus of the hypothalamus, with a K e value of 2.8 nM, and was also anxiolytic in the mouse light/dark box test with a minimum dose of 0.01 mg/kg, s.c. On the contrary, its enantiomer 62 (PD-140,548) was a selective and competitive CCK 1 antagonist, which inhibited the CCK-8-evoked amylase release from rat pancreatic acinar cells with a K e value of 16 nM.…”

Twenty years of non-peptide CCK1receptor antagonists: all that glitters is not gold

“…Similarly, Kissei Pharmaceutical has developed KSG-504 (29, Figure 5) [224], which is a naphthylsulfonylalkanoic acid derivative [65]. Its structure is similar to that of loxiglumide, containing the napthylsulfonylmethyl moiety instead of the benzoylamidic group.…”