Quantitative Structure‐Activity Study of the Inhibition of Acetylcholinesterase with Aliphatic Ammonium Ions

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Abstract
To understand the role of the interaction between the positively charged quaternary nitrogen of the acetylcholine molecule and the anionic site of acetylcholinesterase, we measured the affinity of a number of aliphatic ammonium ions with bovine erythrocyte acetylcholinesterase in terms of the inhibition constant Ki and quantitatively analyzed the affinity index, log (1/Ki), with free‐energy‐related substituent and structural parameters and the multiple regression technique. Since the interaction of ammonium ions with the anionic site is regarded as being a type of ion‐pair formation in a hydrophobic milieu, we expected that the total steric effect of N‐substituents should be similar to that previously studied for the ion‐pair formation‐partition equilibrium of ammonium ions with picrate in the 1‐octanol/water system. By taking all of the steric effect terms in this ion‐pairing system as a single independent variable, the analysis was made to separate the specific hydrophobic effect of four N‐substituents on the affinity from their steric effect. The ammonium ions were suggested to interact with the anionic site so that the hydrophobic interaction of N‐substituents is dependent on their relative size while the total steric congestion is lowest. The hydrophobic nature of the enzymic milieu surrounding the anionic site was not uniform. The NH hydrogens in ions other than the quaternary were shown to lower the inhibitory activity nearly in proportion to their number. Being hydrated, the positively charged NH group could work to hold the ions in the bulk aqueous phase rather than on the enzyme.