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 D(2) or
serotonin 5-HT(4) 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.