Inhibitor Report for: KW-5092

KW-5092 (2-[1-[2-[[5-(piperidinomethyl)-2-furanyl] methylamino]ethyl]imidazonylidin-2-ylidenene]malononitrile fumarate) is a novel gastroprokinetic agent with both acetylcholine release facilitatory and acetylcholinesterase inhibitory activity. We have investigated the effects of KW-5092 on antroduodenal coordination and gastric emptying in guinea-pigs. In the guinea-pig isolated gastroduodenal preparation, KW-5092 at 3 x 10(-7) to 3 x 10(-6) M significantly increased antroduodenal coordination. The effect of KW-5092 was almost completely inhibited by atropine or tetrodotoxin. Cisapride, a gastroprokinetic agent with acetylcholine release facilitatory activity, also increased coordination whereas neither acetylcholine nor the acetylcholinesterase inhibitor neostigmine affected it. In-vivo, KW-5092 and cisapride enhanced gastric emptying whereas neostigmine delayed it. These results suggest that acetylcholine release facilitation, but not acetylcholinesterase inhibition, is involved in the enhancement by KW-5092 of antroduodenal coordination and gastric emptying.

We examined the effect of KW-5092, a gastroprokinetic agent with acetylcholinesterase inhibitory and acetylcholine release facilitatory activities, on the peristalsis of isolated guinea pig ileum. KW-5092 (10(-9)-3 x 10(-6)M) increased the frequency of the peristaltic wave without changing its amplitude. Neostigmine increased the frequency at 10(-7) M, but domperidone (10(-8)-3 x 10(-6)M) had no effect on the peristalsis. The present results suggest that KW-5092 enhances the peristalsis via the inhibition of acetylcholinesterase, resulting in the intestinal propulsion.

KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2-furanyl]- methyl]amino]ethyl]-2-imidazolidinylidene]propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase inhibitory and acetylcholine release facilitatory activity. The present study examined the effects of KW-5092 on the defecation and colonic motor activity in rats. KW-5092, at 1 to 30 mg/kg, p.o., dose-dependently increased the fecal pellet output. In the in vitro study, KW-5092, at 10(-6) M to 10(-5) M, evoked contraction of the isolated distal colonic preparation. In the in vivo study, KW-5092, at 1 to 10 mg/kg, p.o., induced an increase in the distal colonic motor index, which was dose-dependently inhibited by atropine (0.1 to 1 mg/kg, i.v.). The present results suggest that KW-5092 induces the defecation in rats by enhancing the distal colonic motor activity via its acetylcholinesterase inhibitory activity and/or acetylcholine release facilitatory activity. KW-5092 may be a useful drug in the treatment of constipation.

KW-5092 (2-[1-[2-[[5-(piperidinomethyl)-2-furanyl] methylamino]ethyl]imidazonylidin-2-ylidenene]malononitrile fumarate) is a novel gastroprokinetic agent with both acetylcholine release facilitatory and acetylcholinesterase inhibitory activity. We have investigated the effects of KW-5092 on antroduodenal coordination and gastric emptying in guinea-pigs. In the guinea-pig isolated gastroduodenal preparation, KW-5092 at 3 x 10(-7) to 3 x 10(-6) M significantly increased antroduodenal coordination. The effect of KW-5092 was almost completely inhibited by atropine or tetrodotoxin. Cisapride, a gastroprokinetic agent with acetylcholine release facilitatory activity, also increased coordination whereas neither acetylcholine nor the acetylcholinesterase inhibitor neostigmine affected it. In-vivo, KW-5092 and cisapride enhanced gastric emptying whereas neostigmine delayed it. These results suggest that acetylcholine release facilitation, but not acetylcholinesterase inhibition, is involved in the enhancement by KW-5092 of antroduodenal coordination and gastric emptying.

We examined the effect of KW-5092, a gastroprokinetic agent with acetylcholinesterase inhibitory and acetylcholine release facilitatory activities, on the peristalsis of isolated guinea pig ileum. KW-5092 (10(-9)-3 x 10(-6)M) increased the frequency of the peristaltic wave without changing its amplitude. Neostigmine increased the frequency at 10(-7) M, but domperidone (10(-8)-3 x 10(-6)M) had no effect on the peristalsis. The present results suggest that KW-5092 enhances the peristalsis via the inhibition of acetylcholinesterase, resulting in the intestinal propulsion.

KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2-furanyl]- methyl]amino]ethyl]-2-imidazolidinylidene]propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase inhibitory and acetylcholine release facilitatory activity. The present study examined the effects of KW-5092 on the defecation and colonic motor activity in rats. KW-5092, at 1 to 30 mg/kg, p.o., dose-dependently increased the fecal pellet output. In the in vitro study, KW-5092, at 10(-6) M to 10(-5) M, evoked contraction of the isolated distal colonic preparation. In the in vivo study, KW-5092, at 1 to 10 mg/kg, p.o., induced an increase in the distal colonic motor index, which was dose-dependently inhibited by atropine (0.1 to 1 mg/kg, i.v.). The present results suggest that KW-5092 induces the defecation in rats by enhancing the distal colonic motor activity via its acetylcholinesterase inhibitory activity and/or acetylcholine release facilitatory activity. KW-5092 may be a useful drug in the treatment of constipation.

KW-5092 ([1-[2-[[[5-(piperidinomethyl)- 2-furanyl]methyl]amino]ethyl]-2-imidazolidinylidene]propanedini trile fumarate) enhances acetylcholine release from enteric neurons and inhibits acetylcholinesterase (AChE), resulting in the enhancement of a wide range of gastrointestinal motilities. The present study examined the effects of KW-5092 on intestinal water and electrolyte transport in rats. In the jejunum, oral or intrajejunal administration of the laxative bisacodyl (30 mg/kg) significantly inhibited absorption of water, Na+ and Cl-, and significantly enhanced K+ secretion. In contrast, neither KW-5092 (1-30 mg/kg) nor the AChE inhibitor neostigmine (0.3-10 mg/kg), orally or intrajejunally administered, affected water or electrolyte transport in the jejunum. Similar results were obtained in the colon when the drugs were applied orally or intracolonically. Moreover, neither KW-5092 (1-30 mg/kg, p.o.) nor neostigmine (0.3-10 mg/kg, p.o.) induced diarrhea, while bisacodyl (30 mg/kg, p.o.) induced diarrhea in all the rats examined. These results demonstrate that KW-5092 or neostigmine at the gastroprokinetic doses does not affect intestinal water or electrolyte transport in rats, suggesting that cholinergic activation enhances gastrointestinal motility rather than intestinal secretion of water and electrolytes.

KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2- furanyl]methyl]amino]ethyl]-2-imidazolidinylidene] propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase (AChE) inhibitory activity and acetylcholine release facilitatory activity. The present study used guinea pig ileal homogenates to examine the inhibitory effects of KW-5092 on the activities of AChE and butyrylcholinesterase (BCHE). KW-5092 inhibited AChE and BCHE with the IC50 values of 6.8 x 10(-8) M and 2.4 x 10(-5) M, respectively. The IC50 values of neostigmine for AChE and BCHE were 3.6 x 10(-8) M and 1.9 x 10(-7) M, respectively. HSR-803 (N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride), a gastroprokinetic agent, inhibited AChE and BCHE with the IC50 values of 8.6 x 10(-6) M and 6.0 x 10(-4) M, respectively. The AChE inhibition by KW-5092 was reversible and noncompetitive, whereas that by HSR-803 was reversible and uncompetitive. On the other hand, the AChE inhibition by neostigmine was non-competitive when the enzyme was preincubated with this inhibitor for 2 min prior to the addition of the substrate, and it was nearly competitive when the enzyme, the inhibitor and the substrate were incubated simultaneously. The present results demonstrate that KW-5092 is a selective, reversible and noncompetitive inhibitor of AChE with different characteristics from those of neostigmine and HSR-803. The AChE inhibitory action may contribute to its gastroprokinetic effect.