Acotiamide Hydrochloride (Z-338), a New Selective Acetylcholinesterase Inhibitor, Enhances Gastric Motility without Prolonging QT Interval in Dogs: Comparison with Cisapride, Itopride, and Mosapride

Authors:
  • TTTakao Tanaka
    Takao Tanaka
  • KYKoji Yoshinaga
    Koji Yoshinaga
  • SUShigeru Ueki
    Shigeru Ueki
  • YHYuko Hori
    Yuko Hori
  • RERuna Eta
    Runa Eta
  • YKYoshihiro Kawabata
    Yoshihiro Kawabata
  • KYKazuyoshi Yoshii
    Kazuyoshi Yoshii
  • KYKenji Yoshida
    Kenji Yoshida
  • TMToshihiro Matsumura
    Toshihiro Matsumura
  • SFShigeru Furuta
    Shigeru Furuta
  • MTMineo Takei
    Mineo Takei
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Abstract
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.

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