title: Inhibitory effects of KW-5092, a novel gastroprokinetic agent, on the activity of acetylcholinesterase in guinea pig ileum.
abstract: 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 (BuChE). KW-5092 inhibited AChE and BuChE 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 BuChE 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 BuChE 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.
authors.affiliation: Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kishibayashi
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: A
authors.initials: A
authors.lastname: Karasawa
mesh_terms: D000122:Acetylthiocholine / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001593:Benzyl Compounds / Q000494:pharmacology; D002092:Butyrylthiocholine / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D009388:Neostigmine / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D001593:Benzyl Compounds; D002800:Cholinesterase Inhibitors; D007093:Imidazoles; D009124:Muscle Proteins; D009570:Nitriles; C064878:N-(4-(2-(dimethylamino)ethoxy)benzyl)-3,4-dimethoxybenzmide; C081341:KW 5092; D009388:Neostigmine; D000122:Acetylthiocholine; D002092:Butyrylthiocholine