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

作者：Banister Samuel D; Manoli Miral; Barron Melissa L; Werry Eryn L; Kassiou Michael^*

来源：Bioorganic & Medicinal Chemistry, 2013, 21(19): 6038-6052.

DOI：10.1016/j.bmc.2013.07.045

• Sigma receptor
• Hemiaminal
• Trishomocubane
• Nitric oxide
• Neuroprotection

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 sigma 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 sigma 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 sigma(2) receptors. The N-methyl-11-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)] undecan-8-ones demonstrated the poorest sigma 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 sigma 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 sigma ligand with NOS inhibitory activity.

• 出版日期2013-10-1