Pharmacological profile of T-0632, a novel potent and selective CCK A receptor antagonist, in vivo

Abstract

The pharmacological profile of a new CCK A receptor antagonist, T-0632 [sodium ( S)-1-(2-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinylcarbonyl)amino]-6-methoxy-2-oxo-1 H-indole-3-propanoate], was examined in in vivo studies and compared with those of L-364,718 [3 S(−)- N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepine-3-yl)-1 H-indole-2-carboxamide] and loxiglumide [ d,l-4-(3,4-dichlorobenzoylamino)-5-( N-3-methoxypropyl-pentylamino)-5-oxopentanoic acid]. In rats, intravenously administered T-0632, L-364,718 and loxiglumide dose dependently inhibited cholecystokinin octapeptide (CCK-8)-stimulated pancreatic exocrine secretion with estimated ED 50 values of 0.025, 0.016 and 1.8 mg/kg, respectively. The ED 50 values for intraduodenal administration of these compounds were 0.040, 0.26 and 3.0 mg/kg, respectively. In mice, orally administered T-0632 prevented caerulein-induced pancreatitis, CCK-8-induced inhibition of gastric emptying and CCK-8-induced gallbladder emptying in dose-dependent manners with ED 50 values of 0.028, 0.047 and 0.12 mg/kg, respectively. The effect of T-0632 for caerulein-induced pancreatitis was 4-fold more potent than that for gallbladder emptying. In contrast, the effects of L-364,718 and loxiglumide for caerulein-induced pancreatitis were 2–4-fold weaker than those for gallbladder emptying. In dogs, T-0632 and loxiglumide maximally inhibited CCK-8-stimulated pancreatic amylase secretion at doses of 0.01 and 10 mg/kg, respectively. At these doses, the effect of T-0632 on CCK-8-induced increase in the gallbladder intraluminal pressure was weaker than that of loxiglumide. These results suggest that T-0632 has a potent antagonistic action on CCK A receptors in several animal species and the effects of T-0632 are more selective for the pancreas over the gallbladder compared with L-364,718 and loxiglumide