Effects of a New Histamine H2-Receptor Antagonist, Z-300, on Gastric Secretion and Gastro-Duodenal Lesions in Rats: Comparison with Roxatidine.

Abstract

ABSTRACT-We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy] propyl]-2-(2-hydroxyethyl-l-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 < 10-5 M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significant ly 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 in hibited by the compound. The effect persisted for >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-in duced 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 in domethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be most ly related to its potent antisecretory and mucosal-protective activities.

Structural requirements for roxatidine in the stimulant effect of rat gastric mucin synthesis and the participation of nitric oxide in this mechanism

“…The clinical pharmacology of histamine H 2 ‐receptor antagonists and their usefulness in the treatment and prevention of acid‐peptide disorders have been reviewed (Feldman & Burton, 1990a,b). Some of the histamine H 2 ‐receptor antagonists have been reported not only to inhibit acid secretion but also to promote gastric mucosal protection and the so‐called process of cytoprotection (Shiratsuchi et al , 1988; Okabe et al , 1992; Ichikawa et al , 1994a). Compared with the structural requirements and acid‐inhibitory mechanisms for the histamine H 2 ‐receptor antagonists (Ganellin et al , 1976; Durant et al , 1978; Holtje & Batzenschlager, 1990), the chemical aspects for cytoprotective/gastroprotective actions have not been well defined because of the complicated mechanisms of mucosal protection.…”

“…Roxatidine (2‐acetoxy‐ N ‐(3‐[ m ‐(1‐piperidinylmethyl)phenoxy]‐propyl)acetamide hydrochloride), a second‐generation histamine H 2 ‐receptor antagonist (Tarutani et al , 1985) with an increased action on gastric mucosal defense (Shiratsuchi et al , 1988; Okabe et al , 1992), contains both a six‐membered aromatic ring and an amide structure (Figure 1) and has a stimulant effect on corpus mucin biosynthesis in rat gastric mucosa (Ichikawa et al , 1994b). In the first step of the present study, we examined the structural requirements of this drug for the stimulant effect on rat gastric mucin biosynthesis, particularly with regard to whether the cardinal features of roxatidine are only the six‐membered aromatic ring and amide structure, and its relation to histamine H 2 ‐receptor antagonism.…”

Effects of Z-300, a New Histamine H2-Receptor Antagonist, on Mucin Biosynthesis in Rat Gastric Mucosa.

“…1), is a highly selective and competitive histamine H2-receptor antagonist (H2-antagonist) that exhibits potent antisecretory activity in rats and dogs (1). Okabe et al (1) showed that this compound markedly protected the gastric mucosa not only against the patho genesis related to gastric secretion, such as water-immer sion stress, indomethacin or aspirin, but also against HCl • ethanol-induced gastric lesions in rats. This finding suggests that Z-300 may have a so-called cytoprotective action (2) as well as anti-acid secretory activity.…”

Interaction of the New Histamine H2-Receptor Antagonist Pibutidine Hydrochloride with Canine Cloned H2-Receptor Expressed Cells

“…It has been established that these antagonists are useful drugs, for example cimetidine, ranitidine and famotidine, for the treatment of peptic ulcers and acid-related diseases, and that their effects are due to the prevention of gastric acid secretion by the blockade of histamine H z -receptors [2,3]. Subsequently, several Hz-receptor antagonists with different structures have been designed [4,5,6]. We have discovered a new Hz-receptor antagonist, IT-066i) ((Z)-3-amino-4-{4-{4-[(piperidinomethyl) pyrid-2-yl]oxy} but-2-enylamino} cyclobut-3-ene-1,2-dione monohydrochloride, CAS 126463-66-9) (see structure formula) containing a cyclobutenedione moiety, and reported that IT-066 has potent and long-lasting anti-secretory and anti-ulcer action [7,8,9].…”