Tricycloundecane Derivatives as Potential N‐Methyl‐D‐aspartate (NMDA) Receptor and Voltage‐Gated Calcium Channel Modulators

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.

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

“…In a previous study, the calcium modulating effects of a small series of tricycloundecene derivatives via the NMDA receptor and VGCC were reported (Figure 2). The significant activity observed for tricyclo[6.2.1.0 2,7 ]undec-9-ene-3,6-dione (1) was attributed to its structural similarities to MK-801 and the adamantanes [24]. In the present study, a series of novel 4-oxatricyclo[5.2.1.0 2,6 ]dec-8-ene-3,5-dione derivatives (2-13, Figure 3), structurally related to 1, were investigated for their cytotoxic profile, ability to block calcium influx via the NMDA receptor and VGCC, and neuroprotective activities through MPP + -induced neurotoxicity using SH-SY5Y neuroblastoma cells.…”

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

“…[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. It exhibits neuroprotective properties and a good safety profile as demonstrated by several studies.…”

“…In the synthesis of 1, the cycloaddition reaction between p-benzoquinone and monomerised cyclopentadiene yielded an intermediate, which was subsequently selectively reduced by zinc to afford the desired compound in fair yield (Figure 3). 25,26 Figure 3. Synthesis of compound 1.…”