Molecular hybridization of 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity

A series of N-substituted 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4–6) showed good selectivity for σ1 and σ2 receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol (4, σ1Ki = 27 nM, σ2Ki = 55 nM) showed reduced affinity for D1–D5 dopamine receptors when compared to haloperidol itself. The compound with the greatest σ1 affinity in the series, benzamide 4 (σ1Ki = 7.6 nM, σ2Ki = 225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ2 selective parent benzamide, RHM-2 (3, σ1Ki = 10412 nM, σ2Ki = 13.3 nM).

The synthesis of a series of N-substituted 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane-3-ols incorporating subunits from known sigma (σ) receptor ligands, based on a molecular hybridization approach, is reported. In vitro receptor screening reveals the ability of the polycarbocyclic hemiaminal unit to lower off-target affinity for multiple dopamine receptors, and to modulate σ receptor subtype selectivity.Figure optionsDownload as PowerPoint slide