Effects of SK-951, a benzofuran derivative, as a prokinetic agent in rats and dogs.
The gastrokinetic activity of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3-dihy dro-2-methylbenzo[b]furan-7-carboxamide hemifumarate), a benzofuran derivative with 5-hydroxytryptamine (5-HT)4-receptor agonist activity, was studied in rats and dogs. The effects of SK-951 were also investigated in a model of vagotomy-induced gastroparesis in comparison with cisapride. In rats, both SK-951 and cisapride enhanced gastric emptying of liquids (phenol red) at a dose of 1-100 mg/kg, p.o. Gastric emptying of liquid (acetaminophen) in fasted beagle dogs was enhanced significantly by SK-951 (1.0 mg/kg, i.v.), whereas the effect of cisapride (0.2-1.0 mg/kg, i.v.) was not statically significant. Similar results were found when radiopaque markers were given with standard meal to dogs with vagotomy-induced gastroparesis. The delayed gastric emptying of radiopaque markers by vagotomy was reversed by SK-951 (1.0 mg/kg, i.v.), whereas cisapride showed no effect at doses from 0.1 to 1.0 mg/kg, i.v. These results indicated that oral and intravenous administration of SK-951 accelerates gastric emptying of both liquids and solids in animal models. Thus, SK-951 may be a highly potent and useful prokinetic agent in comparison to cisapride.
Takeda
M
M
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Shiosaki, Mie, Japan.
Tsukamoto
K
K
Yamano
M
M
Uesaka
H
H
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects*; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D008297:Male; D010637:Phenolsulfonphthalein / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014628:Vagotomy
D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005765:Gastrointestinal Agents; C113458:SK 951; D017366:Serotonin Receptor Agonists; D010637:Phenolsulfonphthalein