Histamine H_2 : Receptor Antagonism of T : 593, an Anti : ulcer Agent: Studies on Aminopyrine Accumulation in Isolated Canine Gastric Mucosal Cells

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Abstract

Histamine H<SUB>2</SUB>-receptor antagonistic properties of the anti-ulcer agent T-593, (±)-(<I>E</I>)-1-[2hydroxy-2-(4-hydroxyphenyl)ethyl]-3-[2[[[5-(methylamino)methyl-2-furyl]methyl]thio]ethyl]-2-(methylsulfonyl)guanidine, were investigated on [<SUP>14</SUP>C]aminopyrine accumulation in isolated canine gastric mucosal cells and compared with those of ranitidine and famotidine. The potency of T-593-inhibition of [<SUP>14</SUP>C]aminopyrine accumulation stimulated by 10<SUP>-4</SUP> M histamine, with an IC<SUB>50</SUB> value of 1.85× 10<SUP>-6</SUP> M, was approximately 5 times greater than that of ranitidine, but half that of famotidine. T-593 did not affect [<SUP>14</SUP>C]aminopyrine accumulation stimulated by carbachol or dibutyryl-cAMP. T-593 depressed the maximal response of the histamine concentration-response curve with a dose-related displacement to the right, indicating that the nature of the H<SUB>2</SUB>-receptor antagonism of T-593 was insurmountable and included noncompetitive inhibition. The inhibitory efficacy of T-593 was time-dependent and was retained after the cells were washed. The inhibitory potency of (-)-<I>S</I>-T-593, one of the enantiomers, on the [<SUP>14</SUP>C]aminopyrine accumulation stimulated by histamine was approximately twice that of racemic T-593 and it also behaved as an insurmountable H<SUB>2</SUB>-receptor antagonist. However, the potency of (+)-<I>R</I>-T-593 was markedly weak. These results suggest that T-593 has H<SUB>2</SUB>-receptor antagonism that is insurmountable and this agent slowly associates and dissociates with the receptor in isolated canine gastric mucosal cells and that the specific substance causing H<SUB>2</SUB>-receptor antagonism is (-)-<I>S</I>-T-593.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 78(3), 313-322, 1998-11-01

    The Japanese Pharmacological Society

References:  32

Cited by:  1

Codes

  • NII Article ID (NAID)
    10008681223
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    00215198
  • NDL Article ID
    4610820
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  CJPref  NDL  J-STAGE 
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