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

Bioorg Med Chem. 2013 Oct 1;21(19):6038-52. doi: 10.1016/j.bmc.2013.07.045. Epub 2013 Aug 6.


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

Keywords: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkanes / chemical synthesis*
  • Alkanes / chemistry
  • Alkanes / pharmacology
  • Cell Survival / drug effects
  • Humans
  • Ligands
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Nitric Oxide / antagonists & inhibitors
  • Receptors, sigma / agonists*
  • Small Molecule Libraries
  • Structure-Activity Relationship


  • Alkanes
  • Ligands
  • Neuroprotective Agents
  • Receptors, sigma
  • Small Molecule Libraries
  • Nitric Oxide
  • undecane