Faculty Collaboration Database

High-affinity sigma-1 (σ₁) receptor ligands based on the σ₁ antagonist PB212. Future Med Chem 2019 Oct;11(19):2547-2562

Date

10/22/2019

Pubmed ID

31633399

DOI

10.4155/fmc-2019-0042

Scopus ID

2-s2.0-85073634435 (requires institutional sign-in at Scopus site)   6 Citations

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 (K_i.#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.

Author List

Niso M, Mosier PD, Marottoli R, Ferorelli S, Cassano G, Gasparre G, Leopoldo M, Berardi F, Abate C

Author

Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Humans
Models, Molecular
Molecular Structure
Naphthalenes
Optical Imaging
Piperidines
Receptors, sigma
Tumor Cells, Cultured