Masukazu Inoie, Shigeki Marubuchi and Hirotoshi Arai
Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Simookui, Toyama
930-8508, Japan
Abstract: Histamine H2-receptor antagonistic properties
of the anti-ulcer agent T-593, (+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)
ethyl]-3-[2[[[5-(methylamino)methyl-2-furyl]
methyl]thio]ethyl]-2-(methylsulfonyl)guanidine, were investigated on [14C]aminopyrine
accumulation in isolated canine gastric mucosal cells and compared with
those of ranitidine and famotidine. The potency of T-593-inhibition of [14C]aminopyrine
accumulation stimulated by 10-4 M histamine, with an IC50
value of 1.85 x 10-6 M, was approximately 5 times greater than
that of ranitidine, but half that of famotidine. T-593 did not affect [14C]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 H2-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
(-)-S-T-593, one of the enantiomers, on the [14C]aminopyrine
accumulation stimulated by histamine was approximately twice that of racemic
T-593 and it also behaved as an insurmountable H2-receptor antagonist.
However, the potency of (+)-R-T-593 was markedly weak. These results suggest
that T-593 has H2-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 H2-receptor
antagonism is (-)-S-T-593.
Keywords: T-593, Histamine H2-antagonist, Insurmountable antagonism,
Canine gastric mucosal cell, Aminopyrine accumulation