Involvement of metabolites in the inhibitory effects of 2-(4-ethyl-1-piperazinyl)-4-phenylquinoline dimaleate (AD-2646), a new quinoline derivative, on gastric acid secretion. A comparison with tricyclic antidepressants.
AD-2646, 2-(4-ethyl-1-piperazinyl)-4-phenylquinoline dimaleate, is a new quinoline derivative with similar pharmacological properties to tricyclic antidepressants. Its effects on stimulated gastric acid secretion were examined in the perfused stomach of anesthetized rats and compared with those of imipramine or trimipramine. Inhibitory effects of AD-2646, imipramine or trimipramine on 2-deoxy-D-glucose (2-DG)-induced gastric acid secretion were more prominent after intraduodenal application than after subcutaneous application. However, the potency of inhibition by AD-2876 (an active metabolite of AD-2646) of 2-DG-induced gastric acid secretion was not dependent on the route of administration. When applied subcutaneously, AD-2646 did not change gastric acid secretion stimulated by bethanechol (BeCh) or evoked by electrical stimulation of the vagus nerve. When applied intraduodenally, AD-2646 produced a moderate decrease in gastric acid secretion stimulated by BeCh. In contrast, imipramine decreased the BeCh-induced gastric acid secretion when applied subcutaneously, but not intraduodenally. In cobalt chloride-treated rats, inhibitory effects of intraduodenal AD-2646 and imipramine on 2-DG-induced gastric acid secretion were reduced, probably owing to the decreased formation of metabolites. It is suggested that subcutaneous AD-2646 inhibited 2-DG-induced gastric acid secretion mainly via centrally mediated mechanisms and intraduodenal AD-2646 reduced it at least partly via peripherally mediated mechanisms as well as via centrally mediated mechanisms, and that the inhibition was more prominent after intraduodenal application than after subcutaneous application probably because of greater efficiency in the formation of the active metabolites.
Kimura
Y
Y
Department of Drug Evaluation and Toxicological Sciences, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Yano
S
S
Watanabe
K
K
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004386:Duodenum; D004558:Electric Stimulation; D005744:Gastric Acid / Q000378:metabolism*; D007099:Imipramine / Q000494:pharmacology; D007441:Intubation, Gastrointestinal; D008297:Male; D011804:Quinolines; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014630:Vagus Nerve / Q000502:physiology
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D011804:Quinolines; D015363:Quinolones; D003035:Cobalt; C059916:2-(1-piperazinyl)-4-phenylquinolone; C026400:AD 1308; D003847:Deoxyglucose; C018021:cobaltous chloride; D007099:Imipramine