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

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Author(s)

    • KOIZUMI Tomonobu
    • Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • SAITA Yuji
    • Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • MIYAKE Akira
    • Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • NISHIDA Akito
    • Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • YAZAWA Hidenori
    • Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
    • HONDA Kazuo
    • Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

Abstract

We recently isolated a cDNA clone for the human cholecystokinin (CCK)<SUB>B</SUB>/gastrin receptor and permanently expressed this receptor cDNA in NIH-3T3 cells. [<SUP>125</SUP>I]CCK-8 specifically bound to the membrane of the transfectant, and this binding was displaced by unlabeled CCK-8 with an IC<SUB>50</SUB> of 0.32 nM. Treatment of these cells with CCK-8 increased the intracellular Ca<SUP>2+</SUP> concentration with an EC<SUB>50</SUB> of 0.30 nM. Using these cells expressing functional human CCK<SUB>B</SUB>/gastrin receptors, we investigated the pharmacological properties of (<I>R</I>)-1-[2, 3-dihydro-l-(2''-methylphenacyl)-2-oxo-5-phenyl-1<I>H</I>-1, 4-benzodiazepin-3-yl]-3-(3-methylphenyl) urea (YM022), a potent and selective CCK<SUB>B</SUB>/gastrin receptor antagonist in rats. YM022 potently inhibited [<SUP>125</SUP>I] CCK-8 binding to the membrane with an IC<SUB>50</SUB> of 55 pM and CCK-8-induced Ca<SUP>2+</SUP> mobilization with that of 7.4 nM. On the other hand, its racemate and enantiomer more weakly inhibited this binding (IC<SUB>50</SUB> of 110 pM and 11 nM, respectively) and Ca<SUP>2+</SUP> mobilization (IC<SUB>50</SUB> of 18 nM and 94 nM, respectively). These results indicate that YM022 stereoselectively recognizes the human CCK<SUB>B</SUB>/gastrin receptor as a potent antagonist and that the established transfectant is useful for characterization of human CCK<SUB>B</SUB>/gastrin-receptor ligands.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 71(4), 307-313, 1996-08-01

    The Japanese Pharmacological Society

References:  24

Codes

  • NII Article ID (NAID)
    10008189266
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    00215198
  • Data Source
    CJP  J-STAGE 
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