Histamine H2-receptor antagonism of T-593, an anti-ulcer agent: studies on aminopyrine accumulation in isolated canine gastric mucosal cells.
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 non-competitive 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.
Inoie
M
M
Research Laboratories, Toyama Chemical Co., Ltd., Japan.
Marubuchi
S
S
Arai
H
H
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002250:Carbon Radioisotopes; D018679:Cholinergic Agonists / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015738:Famotidine / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D009853:Omeprazole / Q000494:pharmacology; D010418:Pentagastrin / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
D000897:Anti-Ulcer Agents; D002250:Carbon Radioisotopes; D018679:Cholinergic Agonists; D006146:Guanidines; D006635:Histamine H2 Antagonists; D013450:Sulfones; D000632:Aminopyrine; C088837:T 593; D010890:Pirenzepine; D015738:Famotidine; D003994:Bucladesine; D006632:Histamine; D011899:Ranitidine; D002217:Carbachol; D010418:Pentagastrin; D009853:Omeprazole