Oxo-bridged isomers of aza-trishomocubane sigma (σ) receptor ligands: Synthesis, in vitro binding, and molecular modeling

The in vitro σ receptor affinity of aza-trishomocubyl hemiaminals, and their isomeric oxo-bridged analogues, is rationalized using molecular modeling. Isomeric oxo-bridged analogs of aza-trishomocubane sigma (σ) receptor ligands were synthesized and shown to display a reduced affinity for the σ receptor. In the case of phenethyl derivative 4, there was a concomitant introduction of high-affinity for the α 2C adrenergic receptor, and moderate affinity for the dopamine transporter. Molecular modeling was undertaken to rationalize these results.