Photoswitchable Pseudoirreversible Butyrylcholinesterase Inhibitors Allow Optical Control of Inhibition in Vitro and Enable Restoration of Cognition in an Alzheimer's Disease Mouse Model upon Irradiation

To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and the mechanisms by which BChE affects Alzheimer's disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable BChE inhibitors. The compounds were able to specifically influence different kinetic parameters of the inhibition process by light. For one compound, a 10-fold difference in the IC50-values (44.6 nM cis, 424 nM trans) in vitro was translated to an all or nothing response with complete recovery in a murine cognition-deficit AD model at dosages as low as 0.3 mg/kg.

Automated summary

Selective and pseudoirreversible photoswitchable BChE inhibitors were synthesized to investigate their biological functions and the mechanisms by which they affect Alzheimer's disease. One of the compounds showed significant differences in activity both in vitro and in vivo, and exhibited complete recovery in a murine cognition-deficit AD model.