Characterization of functional effects of Z-338, a novel gastroprokinetic agent, on the muscarinic M1, M2, and M3 receptors expressed in Xenopus oocytes

Doi, Yoshiyuki; Murasaki, Osamu; Kaibara, Muneshige; Uezono, Yasuhito; Hayashi, Hideki; Yano, Koji; Taniyama, Kohtaro

doi:10.1016/j.ejphar.2004.10.003

Cited by 19 publications

(19 citation statements)

References 12 publications

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“…Acotiamide has been reported to facilitate ACh release by blocking muscarinic M 1 and M 2 receptors in guinea pig stomach 33,34 . This increased ACh release may also be involved in the prokinetic effects of higher doses of acotiamide in vivo .…”

Section: Discussionmentioning

confidence: 96%

“…Acotiamide has been reported to facilitate ACh release by blocking muscarinic M 1 and M 2 receptors in guinea pig stomach. 33,34 This increased ACh release may also be involved in the prokinetic effects of higher doses of acotiamide in vivo. Meanwhile, Matsunaga et al reported that the K i value of the competitive AChE inhibition activity of this drug (6.1 · 10 )7 ) was approximately 10 times lower than those for muscarinic M 1 and M 2 receptors at 8.4 · 10 )6 and 9.4 · 10 )6 , respectively.…”

Section: Atropine Groupmentioning

confidence: 99%

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Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs

Nagahama

Matsunaga

Kawachi

et al. 2012

Neurogastroenterology Motil

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Section: Discussionmentioning

confidence: 96%

Section: Atropine Groupmentioning

confidence: 99%

Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs

Nagahama

Matsunaga

Kawachi

et al. 2012

Neurogastroenterology Motil

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“…The affinity of Acotiamide for dopamine D 2 receptor was lower than that of other gastroprokinetics. Based on its affinity for muscarinic receptors with antagonistic activities, Acotiamide partly exerts gastroprokinetic activity by enhancement of acetylcholine (ACh) release via antagonism of the M 1 and M 2 muscarinic receptors 15 . Acotiamide also inhibited acetylcholinesterase (AChE) activity, and thus its inhibitory action of AChE may be partly involved in the gastroprokinetic activity.…”

Section: Introductionmentioning

confidence: 99%

A dose‐ranging, placebo‐controlled, pilot trial of Acotiamide in patients with functional dyspepsia

Tack

Masclee

Heading

et al. 2009

Neurogastroenterology Motil

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Impaired gastric accommodation, hypersensitivity to distension and delayed gastric emptying are major pathophysiological mechanisms in functional dyspepsia (FD). Acotiamide (Z-338) was well-tolerated in healthy volunteers. To determine the effect of three doses of Acotiamide on major pathophysiological mechanisms, symptoms, quality of life (QOL) and safety in functional dyspeptics. A phase IIa, randomized, double-blind, placebo-controlled study (14, 21 and 28 days, respectively, for run-in, study drug administration and follow-up). Gastric accommodation, sensitivity to distension and gastric emptying were assessed by barostat and (13)C breath test, symptoms by daily diary cards and QOL by SF-36. A total of 71 patients were enrolled (62 evaluable). There was no effect on gastric emptying and sensitivity to distension. 300 mg was better than placebo for meal accommodation (P = 0.024). 100 mg was better than placebo at week 2 for upper abdominal bloating (P = 0.001) and overall symptom score (P = 0.022), and at week 3 for bloating (P = 0.008) and heartburn (P = 0.041). 100 mg was also better than placebo for QOL (physical function) (P = 0.003). Acotiamide was safe and well-tolerated in patients with FD. The involved mechanism could at least in part depend on an effect on meal-induced accommodation. 100 mg Acotiamide exhibited the potential to improve FD symptoms and QOL. Further studies are indicated.

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“…Peripheral effects include inhibitorion of presynaptic muscarinic cholinergic autoreceptors and cholinesterase inhibition, both leading to increased availability of Ach in the synaptic cleft which probably enhances signal transduction to enteric motor neurons. There is also evidence that it acts as an agonist on an Ach M 5 -like receptor on gastric myocytes [17]. The central effects, in the AP and on afferent vagal fibers, affect motility and counteract some stress-mediated changes in the brainstem [25].…”

Section: Expert Commentarymentioning

confidence: 98%

“…In this study, cDNAs for rat muscarinic M 1 and M 3 receptors and cDNAs for human M 2 receptor were used. The authors concluded that the increased contractility of muscle strips observed with acotiamide may be due to the antagonistic effects on inhibitory presynaptic M 1 and M 2 receptors [17].…”

Section: Basic Pharmacology and Animal Researchmentioning

confidence: 99%

Acotiamide, a novel gastroprokinetic for the treatment of patients with functional dyspepsia: postprandial distress syndrome

Altan¹,

Masaoka²,

Farré³

et al. 2012

Expert Review of Gastroenterology & Hepatology

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Functional dyspepsia (FD) is a highly prevalent condition with major socioeconomic and healthcare impact. To date, no pharmacological treatment for FD has been approved. The Rome consensus proposed to subdivide FD into postprandial distress syndrome (PDS), characterized by meal-related symptoms and epigastric pain syndrome, characterized by pain and burning. Acotiamide (Z-338 or YM443) is a new drug, developed for the treatment of FD. Acotiamide enhances acetylcholine release from enteric neurons through muscarinic receptor antagonism and acetycholinesterase inhibition, thereby enhancing gastric emptying and gastric accommodation. Acotiamide was evaluated in FD in clinical studies in Europe, Japan and the USA, beneficial effects were observed for the PDS symptoms of postprandial fullness and early satiation, with a dose of 100 mg three-times a day. A 4-week placebo-controlled Phase III study in PDS patients in Japan confirmed efficacy of acotiamide in relieving postprandial fullness, early satiation and upper abdominal bloating.

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Characterization of functional effects of Z-338, a novel gastroprokinetic agent, on the muscarinic M1, M2, and M3 receptors expressed in Xenopus oocytes

Cited by 19 publications

References 12 publications

Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs

Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs

A dose‐ranging, placebo‐controlled, pilot trial of Acotiamide in patients with functional dyspepsia

Acotiamide, a novel gastroprokinetic for the treatment of patients with functional dyspepsia: postprandial distress syndrome

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