Comparison of active sites of butyrylcholinesterase and acetylcholinesterase based on inhibition by geometric isomers of benzene-di-N-substituted carbamates.
We have reported that benzene-1,2-, 1,3-, and 1,4-di-N-substituted carbamates (1-15) are characterized as the conformationally constrained inhibitors of acetylcholinesterase and mimic gauche, eclipsed, and anti-conformations of acetylcholine, respectively (J Biochem Mol Toxicol 2007;21:348-353). We further report the inhibition of butyrylcholinesterase by these inhibitors. Carbamates 1-15 are also characterized as the pseudosubstrate inhibitors of butyrylcholinesterase as in the acetylcholinesterase catalysis. Benzene-1,4-di-N-n-hexylcarbamate (12) and benzene-1,4-di-N-n-octylcarbamate (13) are the two most potent inhibitors of butyrylcholinesterase among inhibitors 1-15. These two para compounds, with the angle of 180 degrees between two C(benzene)--O bonds, mimic the preferable anti C--O/C--N conformers for the choline ethylene backbone of butyrylcholine during the butyrylcholinesterase catalysis. The second n-hexylcarbamyl or n-octylcarbamyl moiety of inhibitors 12 and 13 is proposed to bind tightly to the peripheral anionic site of butyrylcholinesterase from molecular modeling. Butyrylcholinesterase prefers para-carbamates to ortho- and meta-carbamates, whereas acetylcholinesterase prefers para- and meta-carbamates to ortho-carbamates. This result implies that the anionic site of butyrylcholinesterase is relatively smaller than that of acetylcholinesterase because meta-carbamates, which may bind to the anionic sites of both enzymes, are not potent inhibitors of butyrylcholinesterase.
Chiou
Shyh-Ying
SY
Department of Neurosurgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
Huang
Chuan-Fu
CF
Hwang
Mei-Ting
MT
Lin
Gialih
G
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001554:Benzene / Q000737:chemistry; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D007536:Isomerism; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D001554:Benzene