Photoswitchable Pseudoirreversible Butyrylcholinesterase Inhibitors Allow Optical Control of Inhibition <i>in Vitro</i> and Enable Restoration of Cognition in an Alzheimer’s Disease Mouse Model upon Irradiation
Matthias Scheiner, Alexandra Sink, Matthias Hoffmann, Cassandre Vrigneau, Erik Endres, Allison Carles, Christoph Sotriffer, Tangui Maurice, Michael Decker
Abstract
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.