K Takeuchi1, T Hirata, H Yamamoto, T Kunikata, M Ishikawa, Y Ishihara. 1. Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan. takeuchi@mb.kyoto-phu.ac.jp
Abstract
BACKGROUND: S-0509, 2-[(tert-butoxycarbonylmethyl) [(m-(carboxy-phenyl)-ureidomethyl-carbonyl]] aminobenzo phenone, was developed as a potent and selective CCKB/gastrin receptor antagonist that does not affect the central nervous system. METHODS: We evaluated the effects of S-0509 on gastric acid secretion and duodenal ulcerogenic and healing responses in rats comparing it with L-365,260, another CCKB/gastrin receptor antagonist. RESULTS: S-0509 (0.1 approximately 10 mg/kg, i.d.) was able to dose-dependently decrease basal acid secretion and inhibit the acid secretory responses induced by both pentagastrin (60 microg/kg/h, i.v.) and peptone (10%, i.g.) but not histamine (4 mg/kg/hr, i.v.) or carbachol (60 microg/kg/h, i.v.). L-365,260 (10 and 30 mg/kg, i.d.) caused only partial a suppression of the acid secretory response to pentagastrin but not to other stimuli, including peptone treatment. On the other hand, a duodenal ulcerogen, mepirizole (200 mg/kg, s.c. ) caused an increase in acid secretion and resulted in penetrating ulcers in the proximal duodenum, and these ulcers gradually healed over 3 weeks. S-0509 significantly inhibited both the acid secretory (> 1.0 mg/kg, i.d.) and ulcerogenic (> 3 mg/kg, p.o.) responses induced by mepirizole when it was given as a pre-treatment. It also promoted significantly the healing of these ulcers (> 3 x 2 mg/kg, p. o.) when it was given twice daily for 14 days. In contrast, L-365, 260 (30 mg/kg) tended to reduce the severity of mepirizole-induced duodenal ulcers, with a slight inhibition of acid secretion, but it caused no influence on the healing response of these ulcers. CONCLUSION: These results confirmed that S-0509 is a selective CCKB/gastrin receptor antagonist with potent antisecretory action in vivo conditions, and further demonstrated that this agent not only prevents the development of duodenal ulcers but also shows healing promoting action on duodenal ulcers, probably through the blockade of CCKB/gastrin receptors.
BACKGROUND:S-0509, 2-[(tert-butoxycarbonylmethyl) [(m-(carboxy-phenyl)-ureidomethyl-carbonyl]] aminobenzo phenone, was developed as a potent and selective CCKB/gastrin receptor antagonist that does not affect the central nervous system. METHODS: We evaluated the effects of S-0509 on gastric acid secretion and duodenal ulcerogenic and healing responses in rats comparing it with L-365,260, another CCKB/gastrin receptor antagonist. RESULTS:S-0509 (0.1 approximately 10 mg/kg, i.d.) was able to dose-dependently decrease basal acid secretion and inhibit the acid secretory responses induced by both pentagastrin (60 microg/kg/h, i.v.) and peptone (10%, i.g.) but not histamine (4 mg/kg/hr, i.v.) or carbachol (60 microg/kg/h, i.v.). L-365,260 (10 and 30 mg/kg, i.d.) caused only partial a suppression of the acid secretory response to pentagastrin but not to other stimuli, including peptone treatment. On the other hand, a duodenal ulcerogen, mepirizole (200 mg/kg, s.c. ) caused an increase in acid secretion and resulted in penetrating ulcers in the proximal duodenum, and these ulcers gradually healed over 3 weeks. S-0509 significantly inhibited both the acid secretory (> 1.0 mg/kg, i.d.) and ulcerogenic (> 3 mg/kg, p.o.) responses induced by mepirizole when it was given as a pre-treatment. It also promoted significantly the healing of these ulcers (> 3 x 2 mg/kg, p. o.) when it was given twice daily for 14 days. In contrast, L-365, 260 (30 mg/kg) tended to reduce the severity of mepirizole-induced duodenal ulcers, with a slight inhibition of acid secretion, but it caused no influence on the healing response of these ulcers. CONCLUSION: These results confirmed that S-0509 is a selective CCKB/gastrin receptor antagonist with potent antisecretory action in vivo conditions, and further demonstrated that this agent not only prevents the development of duodenal ulcers but also shows healing promoting action on duodenal ulcers, probably through the blockade of CCKB/gastrin receptors.