title: Pharmacological profile of T-0632, a novel potent and selective CCKA receptor antagonist, in vitro.
abstract: The pharmacological profile of a new CCKA receptor antagonist, T-0632 [sodium (S)-3-[1-(2-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinyl)-carbonyl] amino-6-methoxy-2-oxo-1-H-indole]propanoate], was examined in in vitro 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)-1H-indole-2-carboxamide] and loxiglumide [D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5- oxopentanoic acid]. T-0632 inhibited the specific binding of [125I]CCK-8 to rat pancreatic CCKA receptor in a concentration-dependent and competitive manner. The Ki value of T-0632 for the CCKA receptor was estimated to be 0.24 nM, which was 23 000-fold less than the Ki value (5600 nM) for guinea pig CCKB receptor. L-364,718 and loxiglumide were 1500- and 64-fold selective for CCKA over CCKB receptor, respectively. T-0632, L-364,718 and loxiglumide inhibited CCK-8 (100 pM)-stimulated amylase release from rat pancreatic acini in a concentration-dependent manner with IC50 values of 5.0 nM, 5.0 nM and 3.0 microM, respectively. In the isolated rabbit gallbladder smooth muscle, T-0632 and loxiglumide competitively inhibited CCK-8-induced contraction with pA2 values of 8.5 and 7.0, respectively. However, L-364,718 showed an apparent non-competitive antagonism. The IC50 values of T-0632, L-364,718 and loxiglumide for CCK-8 (30 nM)-induced contraction were 31 nM, 4.9 nM and 1300 nM, respectively. The inhibitory effects of T-0632 and loxiglumide in gallbladder smooth muscle were readily reversible, but L-364,718 showed a long-lasting inhibition. These results suggest that T-0632 is a potent, reversible and more selective CCKA receptor antagonist compared with L-364,718 and loxiglumide.
authors.affiliation: Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Taniguchi
authors.forename: N
authors.initials: N
authors.lastname: Yazaki
authors.forename: T
authors.initials: T
authors.lastname: Endo
authors.forename: M
authors.initials: M
authors.lastname: Nagasaki
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D020109:Devazepide; D005704:Gallbladder / Q000187:drug effects; D006168:Guinea Pigs; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012844:Sincalide / Q000037:antagonists & inhibitors
chemical_list: D001570:Benzodiazepinones; D006727:Hormone Antagonists; D007211:Indoles; D011949:Receptors, Cholecystokinin; C103722:T 0632; C053737:loxiglumide; D000681:Amylases; D011377:Proglumide; D020109:Devazepide; D012844:Sincalide