Isomeric oxa-bridged analogs of aza-trishomocubane sigma (σ) receptors were synthesized and shown to display a reduced affinity for the σ receptor. In the case of phenethyl deriv. 4, there was a concomitant introduction of high-affinity for the α2C adrenergic receptor, and moderate affinity for the dopamine transporter. Mol. modeling was undertaken to rationalize these results.