Structure-Function Relationships in The Binding of Reversible Inhibitors in the Active-Site Gorge of Acetylcholinesterase

Abstract

Acetylcholinesterase (AChE) terminates transmission at cholinergic synapses by rapid hydrolysis of acetylcholine (ACh) (Quinn, 1987). Anti-cholinesterase agents are used in treatment of various disorders (Taylor, 1990), and have been proposed as therapeutic agents for managing Alzheimer’s disease (AD) (Becker and Giacobini, 1991). The AChE active site contains a catalytic subsite and a so-called `anionic’ subsite, which binds the quaternary group of ACh (Quinn, 1987). A second, ‘peripheral’ anionic site is so named since it is distant from the active site (Taylor and Lappi, 1975). Bisquaternary AChE inhibitors derive their enhanced potency, relative to homologous monoquatemary ligands (Main, 1976), from their ability to span these two `anionic’ sites, which are ca. 14 A apart.