Jpn. J. Pharmacol. 71 (4), 307-313 (1996)

Antagonistic Effect of YM022, an Antiulcer Agent in Rats, on Human Cholecystokinin (CCK)B/Gastrin Receptor

Tomonobu Koizumi, Yuji Saita, Akira Miyake, Akito Nishida, Hidenori Yazawa and Kazuo Honda

Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305, Japan

Abstract: We recently isolated a cDNA clone for the human cholecystokinin (CCK)B/gastrin receptor and permanently expressed this receptor cDNA in NIH-3T3 cells. [125I]CCK-8 specifically bound to the membrane of the transfectant, and this binding was displaced by unlabeled CCK-8 with an IC50 of 0.32 nM. Treatment of these cells with CCK-8 increased the intracellular Ca2+ concentration with an EC50 of 0.30 nM. Using these cells expressing functional human CCKB/gastrin receptors, we investigated the pharmacological properties of (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin- 3-yl]-3-(3-methylphenyl) urea (YM022), a potent and selective CCKB/gastrin receptor antagonist in rats. YM022 potently inhibited [125I]CCK-8 binding to the membrane with an IC50 of 55 pM and CCK-8-induced Ca2+ mobilization with that of 7.4 nM. On the other hand, its racemate and enantiomer more weakly inhibited this binding (IC50 of 110 pM and 11 nM, respectively) and Ca2+ mobilization (IC50 of 18 nM and 94 nM, respectively). These results indicate that YM022 stereoselectively recognizes the human CCKB/gastrin receptor as a potent antagonist and that the established transfectant is useful for characterization of human CCKB/gastrin-receptor ligands.

Keywords: YM022, Cholecystokinin (CCK)-8, CCKB/gastrin receptor, Calcium mobilization, Stable expression

Copyright© The Japanese Pharmacological Society 1996

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