Synthesis of Reversible Inhibitors of Acetylcholinesterase (EC 3.1.1.7)

The synthesis and characterization of some reversible acetylcholinesterase inhibitors are described in detail. They are structurally related to the natural substrate acetylcholine. All of them bear a trimethylammonium moiety as ‘cationic head’. Instead of an electrophilic ester group, the title compounds include a variety of functionalities, such as halide, ether, thioether, epoxide, amide, ketone and a double bond. The substances are thus suited as probes for the investigation of the esteratic subsite of the acetylcholinesterase active center. Most of the synthesized compounds inhibit the enzyme in a competitive manner with inhibition constants in the range of 10^?5 M to 10^?3 M . With respect to acetylcholine (K_D ≤ 10^?5 M and K_m = (1.6±0.5) 10^?4 M ) their affinity to acetylcholinesterase is in the same order of magnitude.