Synthesis and in vitro properties of a powerful quaternary methylphosphonate inhibitor of acetylcholinesterase. A new marker in blood-brain barrier research.

To substantiate reported data and improve the properties of anticholinesterase drugs in blood-brain barrier (B-BB) research, 7-(methylethoxyphosphinyloxy) 1-methyl-quinolinium iodide (MEPQ) was prepared and evaluated as an inhibitor of both acetyl- and butyrylcholinesterase (AChE and BuChE, respectively) from various sources. The second-order rate constants for the inhibition of cholinesterase from eel, mice brain and horse serum at 25 degrees were found to be 5.3 X 10(8), 1.3 X 10(8) and 5.4 X 10(7) M-1 min-1 respectively. The inhibited enzyme could be reactivated by 1-methyl-2-hydroxy iminomethylpyridinium iodide (2-PAM). The two enantiomers of the racemic mixture MEPQ inhibited AChE at similar rates. Low concentrations of AChE could be determined by the residual enzyme activity and by fluorescence measurements of the leaving group, thus suggesting the application of MEPQ as a sensitive titrant of cholinesterase, as well as a potential tool in studying B-BB permeability changes.