Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

Abstract

Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020).

Neuroprotective Effects of Citidine-5-diphosphocholine on Impaired Spatial Memory in a Rat Model of Cerebrovascular Dementia

“…Donepezil powerfully inhibits acetylcholinesterase (17) and elevates acetylcholine concentration in the synapse, which results in increased cholinergic transmission. Previous studies have suggested the donepezil has neuroprotective effects aside from its acetylcholinesterase-inhibiting action through up-regulation of Bcl-2, an anti-apoptotic protein (18), stimulation of nicotinic acetylcholine receptors (19), and inhibition of glycogen synthase kinase-3 (GSK-3) activity (20).…”

“…It is unknown whether donepezil exerts its neuroprotective effect in rats subjected to repeated cerebral ischemia. Induction of the neuroprotective effects of donepezil via the nicotinic acetylcholine receptor in rats subjected to repeated cerebral ischemia may require a higher concentration and/or long-term treatment because the concentration of donepezil showing neuroprotection is higher than the concentration needed to exhibit acetylcholinesterase-inhibiting action in vitro (17,19,20).…”

“…Donepezil is known to ameliorate spatial memory impairment as an acetylcholine esterase inhibitor (17), and some investigators reported donepezil also has neuroprotective effects (18 -20). However, the quantitative evaluation of donepezil on neuronal cell death in repeatedly ischemic rats is still unclear.…”

Synthesis of α-oxycarbanilinophosphonates and their anticholinesterase activities: the most potent derivative is bound to the peripheral site of acetylcholinesterase

“…Acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) and is the most widely used target enzyme in studies with the purpose to synthesize new and more effective therapeutic agents to treat patients with diseases such as Alzheimer's disease (AD) or myasthenia gravis [7][8][9] . Reversible inhibition of brain AChE by anti-AD drugs such as tacrine 10 , donepezil 11 , and huperzine 12 increases the ACh levels and improves neurotransmission in cholinergic synapses 13 . AChE is also used widely as a target in the studies of compounds with insecticidal activities, as all commercially available organophosphate compounds are believed to exert their effects through potent reversible or irreversible inhibition of this enzyme 14 .…”

Síntese de indanos: uma seleção de métodos gerais e eficientes

“…A rigidez e a planaridade são características importantes deste esqueleto, que está presente em diversas moléculas com atividade biológica de interesse, incluindo fármacos em comercialização, como o Indinavir ® um inibidor da HIV-protease 1,2 e o Aricept ® utilizado no tratamento do mal de Alzheimer 3,4 …”