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 (S)-1-(2-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinylcarbonyl) amino]-6-methoxy-2-oxo-1H-indole-3-propanoate], was examined in in vivo studies and compared with those of L-364, 718 [3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-1 H-indole-2-carboxamide] and loxiglumide [D.L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-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 ED50 values of 0.025, 0.016 and 1.8 mg/kg, respectively. The ED50 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 ED50 values of 0.028, 0.04, 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 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.
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan. h-tani@tanabe-co.jp
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H
Taniguchi
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Yazaki
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Yomota
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Shikano
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Endo
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Nagasaki
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002108:Ceruletide / Q000633:toxicity; D020109:Devazepide; D004285:Dogs; D005260:Female; D005746:Gastric Emptying; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced; D011247:Pregnancy; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000494:pharmacology
D001570:Benzodiazepinones; D007211:Indoles; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; C103722:T 0632; C053737:loxiglumide; D002108:Ceruletide; D011377:Proglumide; D020109:Devazepide; D012844:Sincalide