From Structurally Diverse Sigma-1 (σ1) Receptor Reference Ligands to Live-Cell Probes: Fluorescent Phenoxyalkylpiperidines for the Detection of σ1 Receptor

Sigma-1 (σ1) receptor is increasingly recognized as a ‘pluripotent’ chaperone mainly localized at the mitochondrial- associated endoplasmic reticulum membranes, where it contrib- utes to the regulation of several pathophysiological pathways through a not fully undisclosed interactome. σ1 modulation with small molecules is progressively appearing promising against di- verse pathologies that include neurodegenerative, oncology dis- eases and pain. However, only a deeper understanding of its mechanism of action may lead to σ1 full therapeutic exploitation and specific σ1 fluorescent tracers may help towards this direction. Herein, we fluorescently tagged σ1 reference compounds from four structurally diverse classes. The highest affinity green and red -emitting phenoxyalkylpiperidines 36 and 37 optimally probed σ1 receptor in flow cytometry, producing signals dose-dependently decreased by the σ1 reference (+)-pentazocine. The best-performing ligand 36 allowed the imaging of the σ1 receptor by confocal microscopy in diverse cell lines, appearing as a promising tool for advancing the understanding of σ1 receptor.