The inhibition of acetylcholinesterase by quaternary ammonium ions

A study has been made of the hydrolysis of acetylcholine by acetylcholinesterase of red cells, in the presence of a range of monoquaternary ammonium ion i inhibitors CH 3(CH 2) n−1 N+(CH 3) 3Br- and a range of diquaternary ammonium inhibitors Br-(CH 3) 3N+(CH 2) n N+(CH 3 3Br-. Values of K i were evaluated at 20° in 15 cases, where K i is the enzyme-inhibitor dissociation constant. p K i vs. n was a straight line for both series, the slopes of the lines corresponding to changes in the free energy of dissociation per CH 2 group of 310 cal/mole for the monoquaternaries and 730 cal/mole for the diquaternaries. It is suggested that the higher dissociation energy of the diquaternaries is due to their lying flat on the enzyme surface, thus giving rise to a larger dispersion interaction between inhibitor and enzyme. No evidence is forthcoming for a critical spacing of quaternary groups in the diquaternary compound, such as might be associated with a second anionic site in the active centre of the enzyme.