Synthesis of 3-aza[4.4.3]propellanes with high σ₁ receptor affinity

In order to obtain rigid σ₁ receptor ligands with defined orientation of pharmacophoric elements, the azapropellane scaffold was chosen. Schmidt rearrangement of propellan-8-ones 6 and 10 provided 3-azapropellan-4-ones 7 and 11. Benzylation of the secondary lactams 7 and 11 followed by LiAlH₄ reduction furnished the azapropellanes 4a and 4c, respectively. A second hydrophobic element was introduced by transformation of the alcohols 4a into carbamates 4b. The σ₁ affinity of the azapropellanes 4 is strongly dependent on the stereochemistry and the substitution pattern in 12-position. anti-configured azapropellanes anti-4a and anti-4b show higher σ₁ affinity than their syn-configured counterparts syn-4a and syn-4b. Conversion of the alcohol anti-4a into the carbamate anti-4b led to increased σ₁ affinity, but complete removal of the 12-substituent resulted in the highest σ₁ affinity (K_i(4c) = 17 nM). It can be concluded that the propellane scaffold alone is able to form strong lipophilic interactions and stabilize the ligand-σ₁ receptor complex as does usually the primary hydrophobic region.