Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.

Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer’s disease

“…12 was protected with benzyl bromide to yield compound 14. Finally, 12 was carbamoylated using ethylmethylcarbamic chloride to obtain the carbamate 15 [31]. The targeted compounds 2, 16 and 7 were finally obtained by reductive amination between 11 and 13, 14 or 15 (Scheme 3) Compound 16 was deprotected by hydrogenolysis to yield phenol derivatives 6.…”

“…In order to complement the traditional possibility to conceive MTDL by linking [22], fusing or merging structure, we have recently prepared pleiotropic prodrug [31]. A new molecule has been described that allows the release of a 5-HT4R agonist (3) at the cerebral level after activation by AChE [31]. This molecule 4 can inhibit AChE and release an active compound on a second therapeutic target (Figure 2).…”

Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities

“…The 96-well ultraviolet (UV) plate (COSTAR) was from Corning Incorporated (USA). The detailed procedure was described in [ 26 , 27 ].…”

The Mechanism by Which LiCl Attenuates the Impaired Ability of Learning and Memory of APP/PS1 Double Transgenic Mice May Involve Elevating the Expression of a7 Nicotinic Acetylcholine Receptors via Regulation of the Wnt/β-catenin Pathway

“…Potential treatment of AD targeting the nAChRs may not only enhance cognition, but also attenuate other symptoms of this pathology [25,26]. Unfortunately, current pharmacotherapy only decelerates the symptoms of AD transiently.…”