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Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands

ZAMPIERI, DANIELE
•
VIO, LUCIANO
•
FERMEGLIA, MAURIZIO
altro
LAURINI, ERIK
2016
  • journal article

Periodico
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Abstract
In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new σ1 receptor (σ1R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based σ1 ligands, the threedimensional homology model of the σ1R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the σ1R binding cavity was explored, and the effect on σ1R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward σ1 and σ2 receptors were tested. Finally, a representative series of best σ1R binders were assayed for cytotoxic activity on the SH-SY5Y human neuroblastoma cell line. Specifically, the new 4-phenyloxazolidin-2-one derivatives 2b (i.e., (R)-2b and (S)-2b) emerged as potential leads for further development as σ1R agents, as they were found endowed with the highest σ1R affinity (Kiσ1 values in the range 0.95-9.3 nM), and showed minimal cytotoxic levels exhibited in the selected, cell-based test, in line with a σ1R agonist behavior.
DOI
10.1016/j.ejmech.2016.06.001
WOS
WOS:000382269700057
Archivio
http://hdl.handle.net/11368/2875223
info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84976417469
http://www.sciencedirect.com/science/article/pii/S0223523416304780
Diritti
open access
FVG url
https://arts.units.it/request-item?handle=11368/2875223
Soggetti
  • sigma 1 receptor

  • high affinity ligand

  • molecular modeling

  • sigma 1 antagonists

Scopus© citazioni
12
Data di acquisizione
Jun 7, 2022
Vedi dettagli
Web of Science© citazioni
12
Data di acquisizione
Mar 16, 2024
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