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

Abstract

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 σ₁ affinity and low σ₁/σ₂ selectivity (K_iσ₁ ranging from 31.6 nM to 48.5 nM, K_iσ₁/σ₂ = 5–18), while compound 5d exhibited high σ₂ affinity and selectivity (K_iσ₂ = 56.8 nM, K_iσ₁ > 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 σ₂ receptor subtypes in normal and cancer cells.