title: Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands.
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 three-dimensional 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.
authors.affiliation: Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy. Electronic address: dzampieri@units.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Zampieri
authors.affiliation: Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Vio
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy; National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste, Italy. Electronic address: sabrina.pricl@di3.units.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Corrensstrasse 48, University of Münster, 48149 Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Corrensstrasse 48, University of Münster, 48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Department of Life Sciences, Via Valerio 28/1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Romano
authors.affiliation: Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Mamolo
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D017076:Computer-Aided Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D017480:Receptors, sigma / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D008024:Ligands; D017480:Receptors, sigma
keywords: Binding affinity; Cytotoxicity; Molecular modeling; Sigma receptors