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.
Novel Highly Potent and Selective σ1 Receptor Antagonists Related to Spipethiane
PIERGENTILI, Alessandro;AMANTINI, Consuelo;DEL BELLO, FABIO;GIANNELLA, Mario;MATTIOLI, LAURA;PERFUMI, Marina Cecilia;PIGINI, Maria;SANTONI, Giorgio;QUAGLIA, Wilma
2010-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.