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

Abstract

In this study, the carbamate structure of pseudoirreversible 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 halflife 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.

Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer's disease, and fat metabolism

“…Majority of the structure modification performed on the carbamate and carrier moieties are willing to elevate the inhibitory activity and selectivity against BChE, which are mostly reflected on the IC 50 and SI ratio of inhibitors. However, in 2019, Hoffmann et al 190 performed a special modification based on the kinetic investigation. They selected previously reported compound 24 (Figure 11) that could selectively inhibit BChE with high potency, then they replaced the aliphatic heptyl chain by cyclic structures, remaining the carrier scaffold tetrahydroquinazoline unchanged.…”

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

“…Moreover, throughout AD progression there is a reduction of AChE levels and an increase of those of a nonspecific cholinesterase, butyrylcholinesterase (BChE); thus, targeting the latter could result in higher therapeutic efficacy [ 20 ]. Recently, some novel compounds bearing a carbamate moiety have proved to selectively bind to BChE and to act as neuroprotectors in vivo, pointing out a potential advantage for a disease-modifying therapy [ 24 ].…”

Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer’s Disease Treatment

“…Consideration of the neurobiology of BuChE is particularly relevant nowadays in the treatment of neurodegenerative disorders, such as AD. Selective inhibitors of BuChE have been proposed for their potential to treat Alzheimer's disease [4].…”