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

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. New 1-(4-(aryl(methyl)amino)butyl)-heterocyclic derivatives were designed and synthesized in order to evaluate their affinity towards σ receptors by radioligand binding assays. Moreover, in order to investigate their cytotoxic activity, a functional assay was performed. Some of these derivatives showed a remarkable affinity and selectivity towards σ1 receptors and an interesting cytotoxic profile. [Display omitted] •New 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma-1 receptor ligands were designed and synthesized.•Some of new derivatives showed high affinity and high selectivity for the sigma-1 receptor.•In silico affinity predictions were confirmed by experimental data.•We performed a preliminary functional assay in order to verify the cytotoxic effects of new synthesized derivatives.•Compounds featuring a 4-phenyloxazolidin-2-one moiety displayed the best biological profile.