A σ(1) receptor pharmacophore derived from a series of N-substituted 4-azahexacyclo[,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols (AHDs)

Bioorg Med Chem Lett. 2012 Oct 1;22(19):6053-8. doi: 10.1016/j.bmcl.2012.08.046. Epub 2012 Aug 21.


A library of N-substituted 4-azahexacyclo[,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols (AHDs) was synthesized and subjected to competition binding assays at σ(1) and σ(2) receptors, as well as off-target screening of representative members at 44 other common central nervous system (CNS) receptors, transporters, and ion channels. Excluding 3 low affinity analogs, 31 ligands demonstrated nanomolar K(i) values for either σ receptor subtype. Several selective σ(1) and σ(2) ligands were discovered, with selectivities of up to 29.6 times for σ(1) and 52.4 times for σ(2), as well as several high affinity, subtype non-selective ligands. The diversity of structures and σ(1) affinities of the ligands allowed the generation of a σ(1) receptor pharmacophore that will enable the rational design of increasingly selective and potent σ(1) ligands for probing σ(1) receptor function.

Publication types

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

MeSH terms

  • Bridged-Ring Compounds / chemical synthesis
  • Bridged-Ring Compounds / chemistry
  • Bridged-Ring Compounds / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Receptors, sigma / metabolism*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • 4-azahexacyclo(,6).0(3,10).0(5,9).0(8,11))dodecan-3-ol
  • Bridged-Ring Compounds
  • Ligands
  • Receptors, sigma
  • Small Molecule Libraries
  • sigma-1 receptor