PHARMACOLOGICAL PROFILE OF T-0632, A NOVEL POTENT AND SELECTIVE CCKA RECEPTOR ANTAGONIST, IN-VIVO

The pharmacological profile of a new CCKA receptor antagonist, T-0632 [sodium -[(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 -1,4-benzodiazcpine-3-yl)-1H-indole-2-carboxamide] and l oxiglumide )-5-(N-3-methoxypropyl-pentylamino)-5-oxopentanoic acid]. I n rats, intravenously administered T-0632, L-364,718 and loxiglumide d ose dependently inhibited cholecystokinin octapeptide (CCK-8)-stimulat ed pancreatic exocrine secretion with estimated ED(50) values of 0.025 , 0.016 and 1.8 mg/kg, respectively. The ED(50) values for intraduoden al administration of these compounds were 0.040, 0.26 and 3.0 mg/kg, r espectively. In mice, orally administered T-0632 prevented caerulein-i nduced pancreatitis, CCK-8-induced inhibition of gastric emptying and CCK-8-induced gallbladder emptying in dose-dependent manners with ED(5 0) 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 a nd loxiglumide for caerulein-induced pancreatitis were 2-4-fold weaker those for gallbladder emptying. In dogs, T-0632 and loxiglumide maxim ally inhibited CCK-8-stimulated pancreatic amylase secretion at doses of 0.01 and 10 mg/kg, respectively. At these doses, the effect of T-06 32 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 CCKA 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