Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase

Savini, Luisa; Campiani, Giuseppe; Gaeta, Alessandra; Pellerano, Cesare; Fattorusso, Caterina; Chiasserini, Luisa; Fedorko, James M.; Saxena, Ashima

doi:10.1016/s0960-894x(01)00294-3

Cited by 48 publications

(43 citation statements)

References 12 publications

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“…This means that such a change is beneficial for BuChE selectivity. On the basis of the results, the authors claim that in eqBuChE structure there also exists a peripheral binding site [42].…”

Section: Dual Binding Site Derivatives Of Tacrinementioning

confidence: 95%

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Recent Developments in Cholinesterases Inhibitors for Alzheimers Disease Treatment

Musiał

Bajda²,

Malawska

2007

CMC

186

106

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of anti-alzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the development of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group--dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT(3) receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.

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Section: Dual Binding Site Derivatives Of Tacrinementioning

confidence: 95%

“…(8)). [42]. The group focused on introducing several modifications and finding a selective inhibitor of BuChE in order to describe in detail not only its structure but also all its possible binding sites.…”

Section: Dual Binding Site Derivatives Of Tacrinementioning

confidence: 99%

Recent Developments in Cholinesterases Inhibitors for Alzheimers Disease Treatment

Musiał

Bajda²,

Malawska

2007

CMC

186

106

View full text Add to dashboard Cite

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“…Thus, a wide variety of new compounds have been synthesized and a great number have been evaluated as potential AChE inhibitors over the last decades (8)(9)(10)(11)(12)(13). The majority of these compounds are soluble only in an organic solvent, which frequently requires a great number of controls to evaluate the effect per se of the solvent on enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

Effects per se of Organic Solvents in the Cerebral Acetylcholinesterase of Rats

et al. 2005

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Acetylcholinesterase (AChE) was studied in different rat brain regions (cerebellum, hypothalamus, striatum, hippocampus and cortex) in the presence of different organic solvents normally used in the in vitro assay. The organic solvents used were acetone (C3H6O), acetonitrile (C2H3N), ethyl alcohol (C2H6O), isopropyl alcohol (C3H8O), methyl alcohol (CH4O), tert-butyl alcohol (C4H10O) and dimethyl sulfoxide (DMSO, C2H6OS) ranging from 0.6 to 10%. Ethyl and methyl alcohol presented no effect on AChE activity at any of the concentrations and brain structures tested. In the hippocampus, isopropyl alcohol did not demonstrate a significant inhibitory effect, even at high concentrations. Tert-butyl alcohol presented an interesting result, increased AChE activity (P < .05) in the hypothalamus (1.8%), cortex (1.8 and 2.5) and striatum (1.2, 1.8 and 2.5%) and decreased activity at a concentration of 10% in the cortex (P < .05) and striatum (P < .01). Acetone and acetonitrile presented similar results, both significantly inhibiting AChE in all structures (5%, P < .05 and 10%, P < .01). DMSO exhibited a highly inhibitory effect at practically all concentrations tested (P < .01). In conclusion, for testing new compounds on AChE activity in vitro, methyl and ethyl alcohol may be the best organic solvent choice.

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“…synthesized a new series of homodimeric tacrine analogs 19 (Figure 8), which are characterised by a different length and character of the tether [61]. The most potent AChEI was homodimer 6,8-dichlorotacrine 19a .…”

Section: Cholinesterse Inhibitorsmentioning

confidence: 99%

Neuroactive Multifunctional Tacrine Congeners with Cholinesterase, Anti-Amyloid Aggregation and Neuroprotective Properties

et al. 2011

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The review summarizes research into the highly relevant topics of cholinesterase and amyloid aggregation inhibitors connected to tacrine congeners, both of which are associated with neurogenerative diseases. Various opinions will be discussed regarding the dual binding site inhibitors which are characterized by increased inhibitor potency against acetylcholin/butyrylcholine esterase and amyloid formation. It is suggested that these compounds can both raise levels of acetylcholine by binding to the active site, and also prevent amyloid aggregation. In connection with this problem, the mono/dual binding of the multifunctional derivatives of tacrine, their mode of action and their neuroprotective activities are reported. The influence of low molecular compounds on protein amyloid aggregation, which might be considered as a potential therapeutic strategy in the treatment of Alzheimer's disease is also reported. Finally, attention is paid to some physico-chemical factors, such as desolvation energies describing the transfer of the substrate solvated by water, the metal-chelating properties of biometals reacting with amyloid precursor protein, amyloid beta peptide and tau protein.

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Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase

Cited by 48 publications

References 12 publications

Recent Developments in Cholinesterases Inhibitors for Alzheimers Disease Treatment

Recent Developments in Cholinesterases Inhibitors for Alzheimers Disease Treatment

Effects per se of Organic Solvents in the Cerebral Acetylcholinesterase of Rats

Neuroactive Multifunctional Tacrine Congeners with Cholinesterase, Anti-Amyloid Aggregation and Neuroprotective Properties

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