Studies on the interaction of NMDA receptor antagonist memantine with cell membranes: A mini-review

Zambrano, Pablo; Suwalsky, Mario; Jemioła-Rzemińska, Małgorzata; Strzałka, Kazimierz

doi:10.1016/j.cbi.2018.01.022

Cited by 10 publications

(9 citation statements)

References 36 publications

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“…Memantine SSI then would occur when memantine transits from the second site reservoir to the deep site. Due to memantine’s lipophilicity (Chew et al, 2008; del Rio-Sancho et al, 2012; Zambrano et al, 2018), plausible locations of a memantine second site reservoir include the intracellular compartment or the membrane (Blanpied et al, 1997). As discussed above, there is evidence that memantine does not inhibit from the intracellular compartment (Parsons et al, 2008b).…”

Section: Discussionmentioning

confidence: 99%

Effects of Mg2+ on recovery of NMDA receptors from inhibition by memantine and ketamine reveal properties of a second site

2018

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Memantine and ketamine are NMDA receptor (NMDAR) open channel blockers that are thought to act via similar mechanisms at NMDARs, but exhibit divergent clinical effects. Both drugs act by entering open NMDARs and binding at a site deep within the ion channel (the deep site) at which the endogenous NMDAR channel blocker Mg also binds. Under physiological conditions, Mg increases the ICs of memantine and ketamine through competition for binding at the deep site. Memantine also can inhibit NMDARs after associating with a second site accessible in the absence of agonist, a process termed second site inhibition (SSI) that is not observed with ketamine. Here we investigated the effects of 1 mM Mg on recovery from inhibition by memantine and ketamine, and on memantine SSI, of the four main diheteromeric NMDAR subtypes. We found that: recovery from memantine inhibition depended strongly on the concentration of memantine used to inhibit the NMDAR response; Mg accelerated recovery from memantine and ketamine inhibition through distinct mechanisms and in an NMDAR subtype-dependent manner; and Mg occupation of the deep site disrupted memantine SSI in a subtype-dependent manner. Our results support the hypothesis that memantine associates with, but does not inhibit at the second site. After associating with the second site, memantine can either slowly dissociate directly to the extracellular solution, or transit to the deep site, resulting in typical channel block. Memantine's relatively slow dissociation from the second site underlies the dependence of NMDAR recovery from inhibition on both memantine concentration and on Mg.

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Section: Discussionmentioning

confidence: 99%

Effects of Mg2+ on recovery of NMDA receptors from inhibition by memantine and ketamine reveal properties of a second site

2018

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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%

“…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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“…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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Studies on the interaction of NMDA receptor antagonist memantine with cell membranes: A mini-review

Cited by 10 publications

References 36 publications

Effects of Mg2+ on recovery of NMDA receptors from inhibition by memantine and ketamine reveal properties of a second site

Effects of Mg2+ on recovery of NMDA receptors from inhibition by memantine and ketamine reveal properties of a second site

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

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