N-substituted 8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes as σ receptor ligands with potential neuroprotective effects

Several libraries of similarly N-substituted 8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (9), N-methyl-8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (14), and N-methyl-11-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]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[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (8) scaffold. In general, compared to the corresponding 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]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[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes showed reduced affinity but greater selectivity for σ2 receptors. The N-methyl-11-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecan-8-ones demonstrated the poorest σ receptor affinities, suggesting that 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]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.

1,3-di-o-tolylguanidine; 4-phenyl-1-(4-phenylbutyl)piperidine; 5-HT; 5-hydroxytryptamine; CNS; DA; DAT; DTG; HEK; Hemiaminal; IP(3); LPS; MAM; N-methyl-d-aspartate; NE; NET; NMDA; NO; NOS; Neuroprotection; Nitric oxide; PCC; PET; PPBP; ROS; SAfiR; SERT; SPECT; Sigma receptor; Trishomocubane; VGCCs; central nervous system; dopamine; dopamine transporter; human embryonic kidney; inositol-1,4,5-triphosphate; lipopolysccharide; mitochondria-associated endoplasmic reticulum membrane; nitric oxide; nitric oxide synthase; norepinephrine; norepinephrine transporter; positron emission tomography; pyridinium chlorochromate; reactive oxygen species; serotonin transporter; single photon emission computerised tomography; structure–affinity relationship; voltage-gated calcium channels.