Kishibayashi_1994_Jpn.J.Pharmacol_66_397

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.