AS-4370, a new gastrokinetic agent, enhances upper gastrointestinal motor activity in conscious dogs

Abstract

The effects of AS-4370 [4-amino-5-chloro-2-ethoxy-N-(4-(4-fluorobenzyl)-2 morpholinyl)methyl)benzamide citrate] on gastrointestinal (GI) motor activity were compared with those of cisapride and metoclopramide in conscious dogs with force transducers implanted chronically. In postprandial state, AS-4370 given 0.2 to 1 mg/kg i.v. or 1 mg/kg intraduodenally (i.d.) stimulated the antral and duodenal motor activity without affecting the colonic motor activity. Cisapride at 0.2 to 1 mg/kg i.v. or 1 mg/kg i.d. stimulated the motor activity in all sites of the GI tract from the stomach to the colon simultaneously. Metoclopramide, like AS-4370, stimulated the antral and duodenal motor activity, but its effect was less potent than that of AS-4370. AS-4370 did not stimulate the GI motor activity under treatment with atropine but stimulated it under vagotomy. Furthermore, AS-4370 did not potentiate the methacholine-induced antral contraction, whereas neostigmine at 10 micrograms/kg i.v. significantly enhanced it. AS-4370 at 1 mg/kg i.v. did not antagonize the inhibition of antral motor activity induced by i.v. infusion of dopamine (1 mg/kg/hr), whereas cisapride (0.5 mg/kg i.v.) and metoclopramide (1 mg/kg i.v.) antagonized it. In addition, the enhancement of GI motor activity induced by AS-4370 was not prevented by propranolol, prazosin, yohimbine, methysergide, ketanserin, ICS 205-930 or naloxone. 5- Hydroxytryptamine (5-HT) receptor desensitization induced by 5-HT (300 micrograms/kg/hr) in the antrum reduced the enhancement induced by AS-4370.(ABSTRACT TRUNCATED AT 250 WORDS)