4-Nitro-2,1,3-benzoxadiazole derivatives as potential fluorescent sigma receptor probes

New fluorescent derivatives for σ receptors were designed and synthesized. To achieve this purpose, a 4-nitro-2,1,3-benzoxadiazole fluorescent tag was connected through a piperazine linker to a modified skeleton derived from selected σ receptor agonists or antagonists. Compounds 5g , 7b , 7e and 7g displayed high σ 1 affinity and low σ 1 / σ 2 selectivity ( K i σ 1 ranging from 31.6 nM to 48.5 nM, K i σ 1 / σ 2 = 5–18), while compound 5d exhibited high σ 2 affinity and selectivity ( K i σ 2 = 56.8 nM, K i σ 1 > 5000 nM). Binding affinity studies revealed that compounds 5d , 5g , 7b , 7e and 7g showed no affinity towards several receptors including opioid, dopaminergic, serotonergic, adrenergic, muscarinic, histaminergic, N -methyl- d -aspartate (NMDA), NMDA receptor channel, or dopamine and serotonine transporters. The fluorescent properties, cellular uptake and confocal microscopy studies on 5d suggest a potential use of this probe to further clarify the molecular role of σ 2 receptor subtypes in normal and cancer cells.