ANTISECRETORY EFFECTS OF A NOVEL AND LONG-LASTING HISTAMINE H-2-RECEPTOR ANTAGONIST, YM-14471, IN RATS AND DOGS

We investigated some properties of YM-14471 [3-(diethylamino)propyl]-6 -methyl-pyrimidine-4-one trihydrochloride), a new H-2-receptor antagon ist, in comparison with those of famotidine, cimetidine and omeprazole . In guinea pig atria, famotidine and cimetidine produced a competitiv e dose-dependent displacement of histamine-induced tachycardia. In con trast, low concentrations of YM-14471 showed competitive inhibition of tachycardia, whereas high concentrations were irreversible or slowly dissociable. In pylorus-ligated rats, intravenous YM-14471, famotidine and cimetidine dose-dependently inhibited basal gastric secretion wit h ED(50) values of 0.04, 0.43 and 31.2 mg/kg, respectively. ED(50) val ues for oral YM-14471, famotidine, cimetidine and omeprazole were 0.81 , 0.42, 28.9 and 7.7 mg/kg when given at 1 hr before ligation, and 5.7 , 26.7, 1639.5 and 18.6 mg/kg at 5 hr before ligation. In anesthetized dogs, intravenous YM-14471, famotidine, cimetidine and omeprazole als o dose-dependently inhibited histamine (160 mu g/kg.hr)-induced acid s ecretion with ED(50) values of 13.7, 8.7, 333.3 and 65.3 mu g/kg, resp ectively. In Heidenhain pouch dogs, YM-14471 inhibited histamine (40 m u g/kg.hr)-induced acid secretion by both intravenous (0.02 mg/kg) and oral administration (0.3 mg/kg). Moreover, the inhibitory effect of Y M-14471 was more prolonged than those of famotidine and cimetidine by either route, and it was as long as that of omeprazole dosed orally. T hese results suggest that YM-14471 is an irreversible or slowly dissoc iable H-2-receptor antagonist, and has long antisecretory effect.