TY - JOUR T1 - Acotiamide Hydrochloride (Z-338), a New Selective Acetylcholinesterase Inhibitor, Enhances Gastric Motility without Prolonging QT Interval in Dogs: Comparison with Cisapride, Itopride, and Mosapride JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 791 LP - 800 DO - 10.1124/jpet.110.174847 VL - 336 IS - 3 AU - Yugo Matsunaga AU - Takao Tanaka AU - Koji Yoshinaga AU - Shigeru Ueki AU - Yuko Hori AU - Runa Eta AU - Yoshihiro Kawabata AU - Kazuyoshi Yoshii AU - Kenji Yoshida AU - Toshihiro Matsumura AU - Shigeru Furuta AU - Mineo Takei AU - Jan Tack AU - Zen Itoh Y1 - 2011/03/01 UR - http://jpet.aspetjournals.org/content/336/3/791.abstract N2 - Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D2 or serotonin 5-HT4 receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents. ER -