N-substituted 8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes as σ receptor ligands with potential neuroprotective effects

Several libraries of similarly N-substituted 8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes (9), N-methyl-8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes (14), and N-methyl-11-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecan-8-ones (13) were synthesised and screened against a panel of CNS targets in order to develop structure-affinity relationships for cage-modified trishomocubane σ receptor ligands based on the N-substituted 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol (8) scaffold. In general, compared to the corresponding 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols, compounds of type 9 were potent σ receptor ligands with low levels of subtype selectivity, while the corresponding N-methyl-8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes showed reduced affinity but greater selectivity for σ2 receptors. The N-methyl-11-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecan-8-ones demonstrated the poorest σ receptor affinities, suggesting that 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols interact with σ receptors in the bridged hemiaminal form rather than as the non-transannular, aminoketone tautomers. Several compounds of type 8, 9, and 14 were assessed for their ability to inhibit nitric oxide release in vitro, and demonstrated comparable or greater efficacy than 4-phenyl-1-(4-phenylbutyl)piperidine (PPBP), an established neuroprotective σ ligand with NOS inhibitory activity.