We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)
benzoate (Z-300), on the
histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic
gastric ulcers in rats.
Roxatidine acetate hydrochloride (
roxatidine), a known
histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for
Z-300 and
roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to
carbachol.
Z-300, administered either orally or parenterally, significantly inhibited the basal and
histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by
histamine,
pentagastrin or
carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of
histamine-stimulation. Oral
Z-300 significantly protected the gastric mucosa from water-immersion stress-,
indomethacin-,
aspirin- and HCl.
ethanol-induced lesions and protected the duodenal mucosa against
mepirizole- and
cysteamine-induced
ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with
roxatidine.
Z-300, but not
roxatidine, significantly accelerated the
spontaneous healing of
acetic acid ulcers induced in rats and prevented the delay in
ulcer healing caused by
indomethacin. The mechanism of action of
Z-300 on acute lesions and chronic
ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.