A series of novel diastereoisomeric σ ligands 3 was designed, synthesized and 
pharmacologically evaluated. The highly rigid [4.3.3]propellane scaffold was 
used to fix the three dimensional orientation of the pharmacophoric moieties 
required for σ affinity. The syn,syn-configured aminocarbamate syn,syn-3a 
reveals the most promising σ₁ affinity (Ki = 77 nM) and selectivity over the σ₂ 
subtype (21-fold). The σ₂ affinity of all four diastereomers 3 was in the low 
micromolar range. Analysis of the distance between the hydrophobic regions 
(phenyl moieties) of the diastereomers 3 led to the longest range of distances 
(10.3-15.2 Å) for the most potent σ₁ ligand syn,syn-3a, which is in good 
agreement with pharmacophore models.