Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer’s Disease

Xuan, Zhenquan; Gu, Xinmei; Yan, Sicheng; Xie, Yuning; Zhou, Yiying; Zhang, Hui; Jin, Huixia; Hu, Songhua; Mak, Marvin; Zhou, Dongsheng; Tsim, Karl Wah Keung; Carlier, Paul R.; Han, Yifan; Cui, Wei

doi:10.1021/acschemneuro.1c00182

Cited by 10 publications

(6 citation statements)

References 62 publications

(117 reference statements)

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“…Because the number of articles devoted to the development of analogues of THA is enormous, we structured the articles published in 2006–2022 [ 30 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 …”

Section: Summary Of Tacrine-based Hybrids Reported In 2006–2022mentioning

confidence: 99%

Tacrine-Based Hybrids: Past, Present, and Future

Bubley

Erofeev

Gorelkin

et al. 2023

IJMS

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Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the “one drug–multiple targets” strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.

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Section: Summary Of Tacrine-based Hybrids Reported In 2006–2022mentioning

confidence: 99%

Tacrine-Based Hybrids: Past, Present, and Future

Bubley

Erofeev

Gorelkin

et al. 2023

IJMS

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“…The most widely used method is combining the structure of the FDA approved cholinesterase inhibitor with another drug with biological characteristics that is useful for treatment or combined using of several drugs. A new tacrine derivative with acetylcholinesterase inhibition (AChE) and brain-derived neurotrophic factor (BDNF) activation was obtained by linking tacrine with a fragment of huperzine A, and it has been shown to have a cognitive enhancement effect in two kinds of AD mice (APP/PS1transgenic mice and β-amyloid (Aβ) oligomers-treated mice) without inducing significant hepatotoxicity [ 149 ]. However, no relevant clinical trial information was found.…”

Section: Challenges and Opportunities In Developing Marine Natural Pr...mentioning

confidence: 99%

Application of Marine Natural Products against Alzheimer’s Disease: Past, Present and Future

Jin

Hou

et al. 2023

Marine Drugs

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Alzheimer’s disease (AD), a neurodegenerative disease, is one of the most intractable illnesses which affects the elderly. Clinically manifested as various impairments in memory, language, cognition, visuospatial skills, executive function, etc., the symptoms gradually aggravated over time. The drugs currently used clinically can slow down the deterioration of AD and relieve symptoms but cannot completely cure them. The drugs are mainly acetylcholinesterase inhibitors (AChEI) and non-competitive N-methyl-D-aspartate receptor (NDMAR) antagonists. The pathogenesis of AD is inconclusive, but it is often associated with the expression of beta-amyloid. Abnormal deposition of amyloid and hyperphosphorylation of tau protein in the brain have been key targets for past, current, and future drug development for the disease. At present, researchers are paying more and more attention to excavate natural compounds which can be effective against Alzheimer’s disease and other neurodegenerative pathologies. Marine natural products have been demonstrated to be the most prospective candidates of these compounds, and some have presented significant neuroprotection functions. Consequently, we intend to describe the potential effect of bioactive compounds derived from marine organisms, including polysaccharides, carotenoids, polyphenols, sterols and alkaloids as drug candidates, to further discover novel and efficacious drug compounds which are effective against AD.

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“…Finally, the synthesis of dimeric tacrine(10)-hupyridone (A10E), involving the linkage of tacrine with the naturally occurring alkaloid huperzine-A, resulted in an AChE-inhibiting tacrine derivative with additional BDNF activation properties. This compound was shown to prevent cognitive decline and Aβ oligomerization in APP/PS1 mice with higher effectiveness than either substance alone [ 346 ]. Critically, administration of the compound did not result in obvious hepatotoxic effects, which currently limit the lone use of tacrine to treat AD.…”

Section: Boosting Efficacy and Reducing Limitations Of Ad Therapeuticsmentioning

confidence: 99%

Alternative Pharmacological Strategies for the Treatment of Alzheimer’s Disease: Focus on Neuromodulator Function

et al. 2022

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Alzheimer’s disease (AD) is a neurodegenerative disorder, comprising 70% of dementia diagnoses worldwide and affecting 1 in 9 people over the age of 65. However, the majority of its treatments, which predominantly target the cholinergic system, remain insufficient at reversing pathology and act simply to slow the inevitable progression of the disease. The most recent neurotransmitter-targeting drug for AD was approved in 2003, strongly suggesting that targeting neurotransmitter systems alone is unlikely to be sufficient, and that research into alternate treatment avenues is urgently required. Neuromodulators are substances released by neurons which influence neurotransmitter release and signal transmission across synapses. Neuromodulators including neuropeptides, hormones, neurotrophins, ATP and metal ions display altered function in AD, which underlies aberrant neuronal activity and pathology. However, research into how the manipulation of neuromodulators may be useful in the treatment of AD is relatively understudied. Combining neuromodulator targeting with more novel methods of drug delivery, such as the use of multi-targeted directed ligands, combinatorial drugs and encapsulated nanoparticle delivery systems, may help to overcome limitations of conventional treatments. These include difficulty crossing the blood-brain-barrier and the exertion of effects on a single target only. This review aims to highlight the ways in which neuromodulator functions are altered in AD and investigate how future therapies targeting such substances, which act upstream to classical neurotransmitter systems, may be of potential therapeutic benefit in the sustained search for more effective treatments.

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Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer’s Disease

Cited by 10 publications

References 62 publications

Tacrine-Based Hybrids: Past, Present, and Future

Tacrine-Based Hybrids: Past, Present, and Future

Application of Marine Natural Products against Alzheimer’s Disease: Past, Present and Future

Alternative Pharmacological Strategies for the Treatment of Alzheimer’s Disease: Focus on Neuromodulator Function

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