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

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[6.2.1.02,7]undec‐9‐ene‐3,6‐dione (4, 78 %) and 6‐hydroxytricyclo[6.2.1.02,7]undec‐9‐en‐3‐one (5, >95 %) at a concentration of 100 μM. The highest inhibitory activity was observed for 6‐(benzylimino)tricyclo[6.2.1.02,7]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[6.2.1.02,7]undeca‐4,9‐dien‐3‐one (8, 34 %), 9 (38 %) and 2‐(benzylamino)‐3,6‐epoxytricyclo[6.2.1.05,10]undecan‐9‐ol (12, 40 %) showed statistically significant (p