[Studies on histamine H2-receptor antagonistic property of FRG-8813, a novel anti-ulcer drug].
The present study was conducted to investigate the histamine H2-receptor antagonistic property of FRG-8813 by using isolated guinea pig right atria, gastric cells and cerebral cortex preparations. FRG-8813 inhibited the histamine-induced positive chronotropic response of the right atria and shifted the concentration-response curve of histamine to the right with suppression of the maximal response. Although the inhibitory effect of FRG-8813 was enhanced in a time-dependent manner and long-lasting, the antagonism was reversible. The potency of FRG-8813 was 2 times and 50 times greater than those of famotidine and cimetidine, respectively. FRG-8813 decreased the histamine-induced [14C]aminopyrine accumulation in gastric cells. Schild plot analysis showed that the slopes of FRG-8813, famotidine and cimetidine were 1.56, 1.40 and 1.07, respectively, suggesting that the mode of the antagonism of FRG-8813 is also unsurmountable in gastric cells. The lack of effect on dbcAMP- and bethanechol-induced [14C]aminopyrine accumulations indicated the selectivity of FRG-8813 for histamine H2-receptor. As in the right atria, the potency of H2-antagonism was 1.5 times and 40 times greater than those of famotidine and cimetidine, respectively. In the [3H]tiotidine binding study of the cerebral cortex preparation, the Ki values showed that the affinity of FRG-8813 was 2 times and 80 times more potent than those of famotidine and cimetidine, respectively. In conclusion, FRG-8813 is an unsurmountable and selective histamine H2-receptor antagonist with 2 times greater potency than famotidine. The antagonistic activity is reversible in spite of the time-dependent increase of the antagonism.
Inaba
N
N
Pharmaceuticals Research Laboratories, Fujirebio, Inc., Tokyo, Japan.
Shibata
M
M
Onodera
S
S
Tanaka
M
M
Suzuki
T
T
Yamaura
T
T
Ohnishi
H
H
D000081:Acetamides / Q000494:pharmacology*; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D002927:Cimetidine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013997:Time Factors
D000081:Acetamides; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; D000632:Aminopyrine; C076948:lafutidine; D002927:Cimetidine; C023990:tiotidine