Quantitative structure-activity study for inhibition of acetylcholinesterase by m-substituted benzyltrimethylammonium salts.

Inhibition of electric eel AChE by a series of m-substituted benzyltrimethylammonium salts was examined and the inhibition constant of the ammonium ion with the enzyme was quantitatively analyzed with free-energy related substituent parameters and regression techniques. The inhibitory activity was rationalized by a linear combination of pi (hydrophobicity), Es (steric bulkiness), and HB (indicator variable for hydrogen bonding) terms. The existence of a hydrophobic pocket of a certain size on the surface of AChE corresponding to the m-substituent of the ammonium ion was suggested. Structural similarity between the AChE active site and the muscarinic receptor was also indicated by comparing the correlation with that derived for muscarinic activity of the same series of compounds.