AS-4370, a novel gastrokinetic agent free of dopamine D2 receptor antagonist properties.
The gastrokinetic effects of AS-4370, 4-amino-5-chloro-2-ethoxy-N-([4-(4-fluorobenzyl)-2-morpholinyl] methyl) benzamide citrate, were compared with those of metoclopramide in experimental animals. In rats, AS-4370 increased the gastric emptying of a semi-solid meal and of resin pellets at dose ranges of 0.03-30 mg/kg and 1-10 mg/kg p.o., respectively. The minimal effective doses were 3-10 times lower than those of metoclopramide. Gastric emptying, delayed by gastroduodenal surgical intervention, was improved with AS-4370 (0.3-3 mg/kg p.o.). In conscious dogs with strain gauges implanted, AS-4370 (0.5 and 1.0 mg/kg i.v.) enhanced antral and duodenal motility without affecting ileal and colonic motility, indicating a selective enhancing effect on upper gastrointestinal motility. AS-4370 (10(-7) - 3 x 10(-5) M) increased electrically evoked, cholinergically mediated contractions in isolated guinea-pig ileum. AS-4370 (3 mg/kg i.v.) was without effect on gastric acid secretion in anesthetized rats. Unlike metoclopramide, AS-4370 neither depressed the active avoidance response in mice nor the food-reinforced lever pressing response in rats, even at 100 mg/kg p.o. Moreover, AS-4370 (10(-4) M) showed no affinity for D2, alpha 1, alpha 2, 5-HT1 and 5-HT2 binding sites in rat brain synaptic membranes. These results suggest that AS-4370 is a new and potent gastrokinetic agent that lacks dopamine D2 receptor antagonist properties.
Yoshida
N
N
Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Omoya
H
H
Oka
M
M
Furukawa
K
K
Ito
T
T
Karasawa
T
T
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004285:Dogs; D004558:Electric Stimulation; D005744:Gastric Acid / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2
D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; C062720:mosapride; D008787:Metoclopramide