No abstract

Neurodegenerative disorders are debilitating conditions characterised by progressive dysfunction and death of neuronal cells. Amidst the proposed mechanisms of neurodegeneration, the effects of excitotoxicity via N-methyl-D-aspartate (NMDA) receptor stimulation and activation of voltage-gated calcium channels (VGCC) on neuronal cells are prominent. This has led to the development of polycyclic cage molecules such as NGP1-01, which exhibit neuroprotective properties through NMDA receptor and VGCC modulation. The medicinal potential of structurally related tricycloundecanes that are open-cage or rearranged polycyclic moieties has not been explored. This study is therefore focused on the synthesis of a series of novel tricycloundecane derivatives and their ability to inhibit NMDA receptors and VGCC. Significant NMDA receptor inhibition was observed for tricyclo[6.2.1.0(2,7) ]undec-9-ene-3,6-dione (4, 78%) and 6-hydroxytricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (5, >95%) at a concentration of 100 μM. The highest inhibitory activity was observed for 6-(benzylimino)tricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (9, >95%), which is in the same range as the inhibitory activity of MK-801 (dizocilpine). In the VGCC inhibition assay, 6-(benzylamino)tricyclo[6.2.1.0(2,7) ]undeca-4,9-dien-3-one (8, 34%), 9 (38%) and 2-(benzylamino)-3,6-epoxytricyclo[6.2.1.0(5,10) ]undecan-9-ol (12, 40%) showed statistically significant (p<0.05) VGCC inhibition.

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.

No abstract

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.