High-affinity sigma-1 (σ) receptor ligands based on the σ antagonist PB212.

The σ receptor is a druggable target involved in many physiological processes and diseases. To clarify its physiology and derive therapeutic benefit, nine analogs based on the σ antagonist PB212 were synthesized replacing the 4-methylpiperidine with basic moieties of varying size and degree of conformational freedom. 3-Phenylpyrrolidine, 4-phenylpiperidine or granatane derivatives displayed the highest affinity (.#x00A0;= 0.12, 0.31 or 1.03 nM). Calcium flux assays in MCF7σ cells indicated that the highest σ receptor affinity are σ antagonists. Molecular models provided a structural basis for understanding the σ affinity and functional activity of the analogs and incorporated Glennon's σ pharmacophore model. Herein, we identify new compounds exploitable as therapeutic drug leads or as tools to study σ receptor physiology.