Molecular design of multitarget neuroprotectors 3. Synthesis and bioactivity of tetrahydrocarbazole—aminoadamantane conjugates

Соколов, В. Б.; Aksinenko, А. Yu.; Горева, Т. В.; Епишина, Т. А.; Ev, Vinogradov; ́yan, A. V. Gabrel; Vinogradova, Daria V.; Neganova, Margarita E.; Shevtsova, E. F.; Бачурин, С. О.

doi:10.1007/s11172-016-1461-5

Cited by 18 publications

(5 citation statements)

References 16 publications

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“…The same compounds were also evaluated and tested as hydrochlorides with compound 10 that showed the lowest IC 50 value for the ifenprodil site [ 50 ]. Along with this, their effects were studied on the membrane potential of mitochondria, on the Ca 2+ ion-caused depolarization and swelling of mitochondria, both indicating MPT.…”

Section: Memantine and Cholinesterase Inhibitor Hybridsmentioning

confidence: 99%

“…Along with this, their effects were studied on the membrane potential of mitochondria, on the Ca 2+ ion-caused depolarization and swelling of mitochondria, both indicating MPT. These novel compounds depolarize the membrane, indicating that they are toxic; however, exceptions can be made for compounds containing a fluorine as R substituent, which causes just a slight depolarization potential and shows a dose-dependent-inhibiting effect on Ca 2+ ion-induced mitochondrial swelling, thus increasing mitochondrial stability and being assessed as potential neuroprotectors [ 50 ]. Following evaluation of the activity and selectivity of these compounds, molecular docking studies were performed, in order to shed light on the binding poses.…”

Section: Memantine and Cholinesterase Inhibitor Hybridsmentioning

confidence: 99%

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Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

et al. 2020

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Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.

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Section: Memantine and Cholinesterase Inhibitor Hybridsmentioning

confidence: 99%

Section: Memantine and Cholinesterase Inhibitor Hybridsmentioning

confidence: 99%

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

et al. 2020

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“…2 E,F). Thus, Tg-2113x partially inhibits glutamate-induced calcium signal that may be explained by a previously shown effect of this compound on NMDA receptors 51 .…”

Section: Resultsmentioning

confidence: 63%

“…The effectiveness of Tg-2113x in scopolamine-treated animals, and in aged mice can be explored by its ability to modulate the cholinergic system. As we have shown Tg-2113x does not affect the acetylcholine-induced activation of neuronal calcium uptake, but Tg-2113x inhibits butyrylcholinesterase, that catalyzes the hydrolysis of acetylcholine, thereby increasing the choline level essential for memory formation 18 , 51 . The efficacy of selective inhibitors of butyrylcholinesterase as cognitive-stimulating compounds has already been demonstrated by other authors 69 .…”

Section: Discussionmentioning

confidence: 79%

Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and β-amyloid neurotoxicity

Shevtsova

Angelova

Stelmashchuk

et al. 2022

Sci Rep

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All forms of dementia including Alzheimer’s disease are currently incurable. Mitochondrial dysfunction and calcium alterations are shown to be involved in the mechanism of neurodegeneration in Alzheimer’s disease. Previously we have described the ability of compound Tg-2112x to protect neurons via sequestration of mitochondrial calcium uptake and we suggest that it can also be protective against neurodegeneration and development of dementia. Using primary co-culture neurons and astrocytes we studied the effect of Tg-2112x and its derivative Tg-2113x on β-amyloid-induced changes in calcium signal, mitochondrial membrane potential, mitochondrial calcium, and cell death. We have found that both compounds had no effect on β-amyloid or acetylcholine-induced calcium changes in the cytosol although Tg2113x, but not Tg2112x reduced glutamate-induced calcium signal. Both compounds were able to reduce mitochondrial calcium uptake and protected cells against β-amyloid-induced mitochondrial depolarization and cell death. Behavioral effects of Tg-2113x on learning and memory in fear conditioning were also studied in 3 mouse models of neurodegeneration: aged (16-month-old) C57Bl/6j mice, scopolamine-induced amnesia (3-month-old mice), and 9-month-old 5xFAD mice. It was found that Tg-2113x prevented age-, scopolamine- and cerebral amyloidosis-induced decrease in fear conditioning. In addition, Tg-2113x restored fear extinction of aged mice. Thus, reduction of the mitochondrial calcium uptake protects neurons and astrocytes against β-amyloid-induced cell death and contributes to protection against dementia of different ethology. These compounds could be used as background for the developing of a novel generation of disease-modifying neuroprotective agents.

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“…Therefore, the inhibition of particularly BChE activity is very important for overcoming the cholinergic deficit, and it was shown, 180 that BChE inhibitors increase the acetylcholine level in the brain and improve the cognitive functions in rodents, without producing classical adverse effects characteristic of AChE inhibitors 181 . Some adamantane‐containing indoles are ligands of MK801‐ and/or ifenprodil‐binding sites of NMDA glutamate receptors, which can also provide cognitive‐stimulating properties 182 …”

Section: Mitochondria As a Essential Target For Multitarget Neuroactimentioning

confidence: 99%

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

Shevtsova

Maltsev

Vinogradova

et al. 2020

Medicinal Research Reviews

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The mitochondria‐targeting drugs can be conventionally divided into the following groups: those compensating for the energy deficit involved in neurodegeneration, including stimulants of mitochondrial bioenergetics and activators of mitochondrial biogenesis; and neuroprotectors, that are compounds increasing the resistance of mitochondria to opening of mitochondrial permeability transition (MPT) pores. Although compensating for the energy deficit and inhibition of MPT are obvious targets for drugs used in the very early stages of Alzheimer‐like pathology, but their use as the monotherapy for patients with severe symptoms is unlikely to be sufficiently effective. It would be optimal to combine targets that would provide the cognitive‐stimulating, the neuroprotective effects and the ability to affect specific disease‐forming mechanisms. In the design of such drugs, assessment of their potential mitochondrial‐targeted effects is of particular importance. The possibility of targeted drug design for simultaneous action on mitochondrial and neurotransmitter's receptors targets is, in particularly, based on the known interplay of various cellular pathways and the presence of common structural components. Of particular interest is directed search for multitarget drugs that would act simultaneously on mitochondrial calcium‐dependent functions, the targets (receptors, enzymes, etc.) facilitating neurotransmission, and the molecular targets related to the action of so‐called disease‐modifying factors, in particular, the formation and overcoming of the toxicity of β‐amyloid or hyperphosphorylated tau protein. The examples of such approaches realized on the level of preclinical and clinical trials are presented below.

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Molecular design of multitarget neuroprotectors 3. Synthesis and bioactivity of tetrahydrocarbazole—aminoadamantane conjugates

Cited by 18 publications

References 16 publications

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and β-amyloid neurotoxicity

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

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