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    • br Perspectives Given the complexity

    2023-01-28


    Perspectives Given the complexity of the cellular interactome and of protein scaffolding, further progress in revealing how individual membrane proteins, including APP and AChE, interact with each other at various levels, from cell-surface shedding to gene regulation, will clarify some intrinsic mechanisms which allow cell survival under normal and pathological conditions (for summary see Fig. 1). In particular, a deeper understanding of the genetic and epigenetic regulation of the APP-AChE regulatory axis and how to modulate it may provide novel therapeutic strategies in AD.
    Conflict of interest
    Introduction Alzheimer's disease (AD) is the most common cause of dementia characterized among other things by the central cholinergic depletion and amyloid-β (Aβ) plaques [1,2]. So far, the use of acetylcholinesterase (AChE) inhibitors has dominated the symptomatic treatment in early-to-moderate AD [3]. There are currently three marketed drugs, namely donepezil, rivastigmine and galantamine. These three molecules, associated in some cases with memantine (NMDA antagonist glutamate) are the only therapeutic arsenal commercially available. Much efforts have been devoted these last years to develop dual binding site AChE inhibitors that simultaneously bind to both catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]]. Indeed, it was postulated that PAS of the enzyme binds to the nonamyloidogenic form of Aβ protein inducing conformational changes and subsequent amyloid fibril formation [[21], [22], [23]]. As a result, these new AChE inhibitors are expected to exhibit a better pharmacological profile in that they may not only alleviate cognitive deficits but also slow down the progression of AD by inhibiting the Aβ peptide aggregation. Although these findings triggered a renewed interest in the development for AChE inhibitors, the fact remains that peripheral activity commonly encountered with AChE inhibitors causes severe adverse effects and limit seriously their therapeutic efficiency [24]. To address this issue, we recently reported “biooxidisable” prodrugs 1 derived from rivastigmine with the aim at improving Galanthamine HBr delivery and therapeutic efficacy of AChE inhibitors [25,26]. This prodrug approach is based on the masking of a positive charge which is involved in a cation-π interaction with Trp84 within the catalytic site of AChE. In contrast to rivastigmine, it is hypothesized that the dihydroquinoline prodrug 1 remains unprotonated at physiological pH, thus masking the crucial positive charge while ensuring a good lipophilicity to cross the blood-brain barrier (BBB). Once in the brain, oxidation of the dihydroquinoline 1 would unmask the permanent positive charge to restore central AChE inhibition while avoiding the resulting quinolinium salt 2 to cross back the BBB by passive diffusion (Fig. 1a). Although most carbamate quinolinium salts 2 were potent against hAChE (IC50 up to 10 nM), all corresponding 1,4-dihydroquinolines proved to be unable to inhibit hAChE (IC50 > 10 μM), providing an in vitro proof of concept of this prodrug approach. In this context, we report herein the rational design of new central dual binding site AChE inhibitors 4 by exploiting this “biooxidisable” prodrug approach as depicted in Fig. 1b. These dual binding site AChE inhibitors are expected to restore the cholinergic transmission and prevent the aggregation of Aβ, all the while avoiding deleterious peripheral effects frequently encountered in the treatment of AD.
    Results and discussion
    Conclusion From our previous work dealing with central pseudo-irreversible AChE inhibitors based on a redox-activated prodrug strategy [25,26], a new quinolinium-phtalimide heterodimeric ligand 4 was designed to simultaneously interact with both the active and peripheral sites of AChE. By means of a SAR study of diverse synthesized quinolinium salts 2a-p and a molecular docking simulation of compounds 2h, 2j, 2k and 2p, we could determine which position of the quiniolium ring is the most suitable to attach the PEG linker so that the phtalimide fragment at its end is able to interact with the PAS of hAChE. After docking simulation of the designed heterodimer 4 in hAChE showing a possible dual-site binding fashion, ligand 4 was efficiently prepared and revealed to be highly potent against hAChE activity (IC50 = 6 nM) while the corresponding prodrug 3 turned out to be inactive (IC50 > 10 μM). Moreover, a propidium competition assay confirms the interaction of compound 4 at the PAS inducing Aβ (1–42) self-aggregation inhibitory activities. All together, these findings pave the way for the development of novel and side-effects free prodrugs of potent dual binding site AChE inhibitors for the treatment of amnesic disorders like Alzheimer disease.