Comparison of active sites of butyrylcholinesterase and acetylcholinesterase based on inhibition by geometric isomers of benzene‐di‐ N ‐substituted carbamates

Abstract 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° between two C(benzene)O bonds, mimic the preferable anti CO/CN 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. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:303–308, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20286