Screening of novel 3α5β-neurosteroids for neuroprotective activity against glutamate- or NMDA-induced excitotoxicity

Šmídková, Markéta; Hájek, Miroslav; Adla, Santosh Kumar; Slavı́ková, Barbora; Chodounská, Hana; Matoušová, Marika; Mertlíková‐Kaiserová, Helena; Kudová, Eva

doi:10.1016/j.jsbmb.2019.03.007

Cited by 9 publications

(13 citation statements)

References 37 publications

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“…In this study, the SwissADME web tool [ 42 ] was used to predict the drug-likeness and pharmacokinetic properties of amantadine, memantine and 1 – 13 . The adamantanes were included as reference compounds, because they are approved drugs for the treatment of neurodegenerative disorders [ 10 , 11 , 12 , 13 ]. The data generated are presented in Figure 9 and Table 3 .…”

Section: Resultsmentioning

confidence: 99%

“…Compound 2 was the most cytotoxic towards neuroblastoma cell as indicated by the percentage cell viability of 51.02 ± 0.86%. However, the incorporation of various amine moieties (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) In general, all compounds except 3, 6 and 10, showed a decrease in cell viability as the concentrations increased. The increase in cell viability with an increase in concentration, as observed for 3, 6 and 10, may be due to these molecules being able to reduce baseline apoptotic processes within the cells or show proliferative effect in the neuroblastoma cells, especially compound 6.…”

Section: Cytotoxicity Studiesmentioning

confidence: 95%

“…amantadine and memantine (Figure 1), are clinically well tolerated for the treatment of Parkinson's disease and Alzheimer's disease, respectively, due to their atypical mechanism of action on the NMDA receptors [10][11][12][13]. In contrast to MK-801, they exhibit moderate affinity towards the phencyclidine binding site of the NMDA receptor channels to effectively block the NMDA receptor while demonstrating minimal adverse effects [13].…”

Section: Of 16mentioning

confidence: 99%

“…However, they are marked by undesirable psychotomimetic side effects such as hallucination, psychosis, dysphoria and amnesia and are thus unsuitable for clinical purposes. On the other hand, adamantanes, such as amantadine and memantine ( Figure 1 ), are clinically well tolerated for the treatment of Parkinson’s disease and Alzheimer’s disease, respectively, due to their atypical mechanism of action on the NMDA receptors [ 10 , 11 , 12 , 13 ]. In contrast to MK-801, they exhibit moderate affinity towards the phencyclidine binding site of the NMDA receptor channels to effectively block the NMDA receptor while demonstrating minimal adverse effects [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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4-Oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Derivatives as NMDA Receptor- and VGCC Blockers with Neuroprotective Potential

et al. 2020

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The impact of excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptor overactivation and voltage gated calcium channel (VGCC) depolarization is prominent among the postulated processes involved in the development of neurodegenerative disorders. NGP1-01, a polycyclic amine, has been shown to be neuroprotective through modulation of the NMDA receptor and VGCC, and attenuation of MPP+-induced neurotoxicity. Recently, we reported on the calcium modulating effects of tricycloundecene derivatives, structurally similar to NGP1-01, on the NMDA receptor and VGCC of synaptoneurosomes. In the present study, we investigated novel 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives for their cytotoxicity, neuroprotective effects via attenuation of MPP+-induced neurotoxicity and calcium influx inhibition abilities through the NMDA receptor and VGCC using neuroblastoma SH-SY5Y cells. All compounds, in general, showed low or no toxicity against neuroblastoma cells at 10–50 µM concentrations. At 10 µM, all compounds significantly attenuated MPP+-induced neurotoxicity as evident by the enhancement in cell viability between 23.05 ± 3.45% to 53.56 ± 9.29%. In comparison to known active compounds, the derivatives demonstrated mono or dual calcium modulating effect on the NMDA receptor and/or VGCC. Molecular docking studies using the NMDA receptor protein structure indicated that the compounds are able to bind in a comparable manner to the crystallographic pose of MK-801 inside the NMDA ion channel. The biological characteristics, together with results from in silico studies, suggest that these compounds could act as neuroprotective agents for the purpose of halting or slowing down the degenerative processes in neuronal cells.

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Section: Resultsmentioning

confidence: 99%

Section: Cytotoxicity Studiesmentioning

confidence: 95%

Section: Of 16mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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4-Oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Derivatives as NMDA Receptor- and VGCC Blockers with Neuroprotective Potential

et al. 2020

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“…The activities and clinical tolerabilities of the adamantanes are attributed to their ability to uncompetitively block NMDA receptors while displaying minimal adverse effects. [15][16][17][18] Over the past few decades, a number of structurally-related polycyclic cage amines have been synthesised. [19][20][21][22][23][24][25][26] A very good example is NGP1-01, a multifuctional neuroprotective agent that displayed dual attenuation of calcium entry in neuronal cells by blocking NMDA receptors and VGCCs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives as lead scaffolds for neuroprotective agents

Egunlusi¹,

Malan²,

Joubert³

2020

Arkivoc

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Neurodegenerative disorders are characterised by progressive loss of neuronal functions. Of the proposed mechanisms, excitotoxicity, mediated by prolonged glutamate activation and calcium overload, is prominent. NGP1-01, a polycyclic cage amine, and tricyclo[6.2.1.0 2,7 ]undec-9-ene-3,6-dione have been shown to display calcium-modulating properties. In this study, we synthesised structurally-related 4-oxatricyclo[5.2.1.0 2,6 ]dec-8ene-3,5-dione as the base scaffold, and incorporated various functional moieties through aminolysis, to afford a series of imide derivatives. All final compounds were obtained in yields between 47-97% and their structures were confirmed by NMR, IR and MS. These structurally-related derivatives could potentially act as neuroprotective agents. Additionally, their synthetic versatilities could make them precursors, as lead compounds, to potential pharmacologically-active agents.

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Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection

Magdaleno Roman,

Chapa González

2024

Neuroprotection

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Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders. The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders. The dysregulation of glutamate signaling, leading to excitotoxicity and neuronal cell death, has been a focal point in understanding the underlying mechanisms of these conditions. This has prompted a paradigm shift in neuroprotection research, with a growing emphasis on targeting ionotropic glutamate receptors (iGluRs) to restore glutamatergic homeostasis. This review provides a comprehensive overview of recent advancements in the field of iGluR‐targeted neuroprotection. We further investigate the implications of glutamate dysregulation in the central nervous system (CNS) disorders, highlighting the complex interplay between excitotoxicity and neuroprotection. We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage, emphasizing the need for innovative therapeutic approaches. This review provides an extensive survey of the burgeoning field of iGluR‐targeted neuroprotection. It showcases the significant potential of a wide array of compounds, encompassing both natural and synthetic agents, to modulate iGluRs and ameliorate excitotoxicity and oxidative stress‐induced neuronal damage. These compounds have demonstrated impressive neuroprotective effects in diverse experimental models, from glutamate‐induced toxicity to traumatic brain injuries. We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation, heralding a promising era in neuroprotection and CNS disorder management.

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Screening of novel 3α5β-neurosteroids for neuroprotective activity against glutamate- or NMDA-induced excitotoxicity

Cited by 9 publications

References 37 publications

4-Oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Derivatives as NMDA Receptor- and VGCC Blockers with Neuroprotective Potential

4-Oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Derivatives as NMDA Receptor- and VGCC Blockers with Neuroprotective Potential

Synthesis of 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives as lead scaffolds for neuroprotective agents

Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection

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