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

Aim: The σ ₁ 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 ₁ antagonist PB212 were synthesized replacing the 4-methylpiperidine with basic moieties of varying size and degree of conformational freedom. Results & methodology: 3-Phenylpyrrolidine, 4-phenylpiperidine or granatane derivatives displayed the highest affinity ( K _i .#x00A0;= 0.12, 0.31 or 1.03 nM). Calcium flux assays in MCF7σ ₁ cells indicated that the highest σ ₁ receptor affinity are σ ₁ antagonists. Molecular models provided a structural basis for understanding the σ ₁ affinity and functional activity of the analogs and incorporated Glennon's σ ₁ pharmacophore model. Conclusion: Herein, we identify new compounds exploitable as therapeutic drug leads or as tools to study σ ₁ receptor physiology.