High-affinity sigma-1 (σ1) receptor ligands based on the σ1 antagonist PB212.

Journal: Future Medicinal Chemistry
Published:
Abstract

Aim: The σ1 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 σ1 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 (Ki.#x00A0;= 0.12, 0.31 or 1.03 nM). Calcium flux assays in MCF7σ1 cells indicated that the highest σ1 receptor affinity are σ1 antagonists. Molecular models provided a structural basis for understanding the σ1 affinity and functional activity of the analogs and incorporated Glennon's σ1 pharmacophore model.

Conclusion: Herein, we identify new compounds exploitable as therapeutic drug leads or as tools to study σ1 receptor physiology.

Authors
Mauro Niso, Philip Mosier, Roberta Marottoli, Savina Ferorelli, Giuseppe Cassano, Giuseppe Gasparre, Marcello Leopoldo, Francesco Berardi, Carmen Abate