Novel Highly Potent and Selective σ1 Receptor Antagonists Related to Spipethiane

Conservative chemical modifications of the core structure of the lead spipethiane (1) afforded novelpotent σ1 ligands. σ1 affinity and σ1/σ2 selectivity proved to be favored by the introduction of polar functions (oxygen atom or carbonyl group) in position 3 or 4 (4-6) or by the elongation of the distance between the two hydrophobic portions of the molecule with the simultaneous presence of a carbonyl group in position 4 (8 and 9). The observed cytostatic effect against the human breast cancer cell line MCF-7/ADR, highly expressing σ1 receptors, and not against MCF-7, as well as the enhancement of morphine analgesia highlighted the σ1 antagonist profile of this series of compounds. In particular, due to its high σ1 affinity (pKi = 10.28) and σ1/σ2 selectivity ratio (29510), compound 9 might be a novel valuable tool for σ receptor characterization and a suitable template for the rational design of potential therapeutically useful σ1 antagonists.