Highly Selective Butyrylcholinesterase Inhibitors with Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer’s Disease Mouse Model

In this study, the carbamate structure
of pseudo-irreversible butyrylcholinesterase
(BChE) inhibitors was optimized with regard to a longer binding to
the enzyme. A set of compounds bearing different heterocycles (e.g.,
morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and
alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle)
in the carbamate residue was synthesized and characterized in vitro
for their binding affinity, binding kinetics, and carbamate hydrolysis.
These novel BChE inhibitors are highly selective for hBChE over human acetycholinesterase (hAChE), yielding
short-, medium-, and long-acting nanomolar hBChE
inhibitors (with a half-life of the carbamoylated enzyme ranging from
1 to 28 h). The inhibitors show neuroprotective properties in a murine
hippocampal cell line and a pharmacological mouse model of Alzheimer’s
disease (AD), suggesting a significant benefit of BChE inhibition
for a disease-modifying treatment of AD.