Centrally mediated inhibitory effect of 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4- b]pyridine trihydrochloride (KW-5805) on gastric acid secretion in rats.
KW-5805, 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4- b]pyridine trihydrochloride, is a new tricyclic compound with antiulcer activities. Its effect on stimulated gastric acid secretion was investigated in the perfused stomach of anesthetized rats. KW-5805 at 0.3-10 mg/kg, i.v., dose-dependently inhibited gastric acid secretion stimulated by 2-deoxy-D-glucose (2-DG). On the other hand, the compound at 10-20 mg/kg, i.v., exerted a moderate decrease in gastric acid secretion stimulated by bethanechol; and at 10 mg/kg, i.v., it produced no change in gastric acid secretion evoked peripherally by vagal electrical stimulation. When applied intracerebroventricularly at 1-5 micrograms/rat, this compound dose-relatedly reduced gastric acid secretion stimulated by 2-DG. Three main metabolites (KF-10504, KF-9530 and KF-10847) of KW-5805 at 1 mg/kg, i.v., caused no significant decrease in gastric acid secretion stimulated by 2-DG. Doxepin, a tricyclic compound, definitely depressed the 2-DG stimulated gastric acid secretion at 1 mg/kg, i.v. It is suggested that intravenous administration of KW-5805 inhibits gastric acid secretion stimulated by 2-DG, mainly via centrally mediated mechanisms, and that biotransformation of KW-5805 to the metabolites contributes little to the development of the antisecretory effect.
Yano
S
S
Department of Drug Evaluation and Toxicological Sciences, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Kimura
Y
Y
Horie
S
S
Ito
K
K
Yamada
N
N
Mizuno
M
M
Watanabe
K
K
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001584:Benzoxepins / Q000494:pharmacology*; D001626:Bethanechol Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003847:Deoxyglucose / Q000494:pharmacology; D004316:Doxepin / Q000494:pharmacology; D004558:Electric Stimulation; D005744:Gastric Acid / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014630:Vagus Nerve / Q000502:physiology
D000897:Anti-Ulcer Agents; D001584:Benzoxepins; D001626:Bethanechol Compounds; C055432:KW 5805; D004316:Doxepin; D003847:Deoxyglucose