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

Autor:	Giuseppe Gasparre, Marcello Leopoldo, Carmen Abate, Savina Ferorelli, Francesco Berardi, Giuseppe Cassano, Roberta Marottoli, Mauro Niso, Philip D. Mosier
Rok vydání:	2019
Předmět:	Pharmacology 0303 health sciences Sigma-1 receptor Molecular model Chemistry Druggability Antagonist Sigma σ1 receptor Sigma ligands 03 medical and health sciences 0302 clinical medicine Biochemistry 030220 oncology & carcinogenesis Drug Discovery Molecular Medicine 030304 developmental biology
Zdroj:	Future Medicinal Chemistry. 11:2547-2562
ISSN:	1756-8927 1756-8919
DOI:	10.4155/fmc-2019-0042
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::76c8326080ed54a58a9e57010f58daab https://doi.org/10.4155/fmc-2019-0042 Zobrazit plný text záznamu