Design, synthesis and receptor affinity of novel conformationally restricted σ ligands based on the [4.3.3]propellane scaffold

Abstract

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.