Histamine H2-receptor antagonistic action of N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)acetoxyacetamide hydrochloride (TZU-0460).

The antagonism of histamine H2-receptor by N-(3-[3-(1-piperidinylmethyl)phenoxy)propyl)acetoxyacetamide hydrochloride (TZU-0460) was estimated on isolated guinea-pig right atrium and rat uterus in vitro and on gastric acid secretion in dog with Heidenhain pouch. The concentration-response curves for the positive chronotropic effect of histamine and dimaprit (S-[3-(N,N-dimethylamino) propyl]isothiourea) on atrium were displaced to the right in parallel without change in the maximum response by TZU-0460 with pA2 values of 6.56 and 6.74 and also for the relaxant effect on uterus with pA2 values of 6.81 and 6.65, respectively. There was no significant difference between the estimated pA2 values for TZU-0460 on the different tissues against the same agonist, and also between the pA2 values on the same tissue against the different agonists. The slope of the regression line of log (DR-1) against log TZU-0460 concentration on either tissue was not significantly different from unity; 0.98 (95% confidence limits, 0.81-1.14) on atrium, 0.95 (0.56-1.34) on uterus. These results indicate that TZU-0460 is a competitive antagonist of histamine and dimaprit in vitro. In Heidenhain pouch dog, TZU-0460 also competitively antagonized the stimulation of acid secretion by histamine with pA2 of 6.59 and by dimaprit with pA2 of 6.52, calculated on infused rates. These results indicate that TZU-0460 was about 6 times more potent than cimetidine.