From Structurally Diverse Sigma-1 (σ1) Receptor Reference Ligands to Live-Cell Probes: Fluorescent Phenoxyalkylpiperidines for the Detection of σ1 Receptor
Abstract Sigma-1 (σ1) receptor is increasingly recognized as a ‘pluripotent’ chaperone mainly localized at the mitochondrial-associated endoplasmic reticulum membranes, where it contributes to the regulation of several pathophysiological pathways through a not fully undisclosed interactome. σ1 modulation with small molecules is progressively appearing promising against diverse pathologies that include neurodegenerative, oncology diseases 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.
Authors
- Chiara Riganti (ORCID: https://orcid.org/0000-0001-9787-4836)
- Mariachiara Mammone (ORCID: https://orcid.org/0009-0008-6283-7312)
- María Majellaro (ORCID: https://orcid.org/0000-0003-3490-7703)
- Claudia Gioé-Gallo (ORCID: https://orcid.org/0000-0002-2075-6863)
- Maria Grazia Perrone (ORCID: https://orcid.org/0000-0003-4195-5228)
- Tina Spalholz
- Petra Heffeter (ORCID: https://orcid.org/0000-0001-6401-8646)
- Mauro Niso (ORCID: https://orcid.org/0000-0002-2846-1744)
- Roberto Barbaro (ORCID: https://orcid.org/0000-0002-1328-9742)
- Ago Rinken (ORCID: https://orcid.org/0000-0002-7238-749X)
- Winnie Deuther‐Conrad (ORCID: https://orcid.org/0000-0003-3168-3062)
- Francesca Serena Abatematteo (ORCID: https://orcid.org/0000-0001-6297-6234)
- Giovanni Graziano (ORCID: https://orcid.org/0000-0002-5575-3240)
- Carmen Abate (ORCID: https://orcid.org/0000-0001-9292-884X)
- Emiliano Altamura (ORCID: https://orcid.org/0000-0003-3171-6645)
- Eddy Sotelo (ORCID: https://orcid.org/0000-0001-5571-2812)
- Joanna Kopecka (ORCID: https://orcid.org/0000-0003-3612-3953)
- Matilde Colella (ORCID: https://orcid.org/0000-0002-9584-7030)
- Marialessandra Contino (ORCID: https://orcid.org/0000-0002-0713-3151)
- Sandra Ortigueira
- Anselma Liturri (ORCID: https://orcid.org/0009-0005-3291-8910)
- Bianca Stiller
- Gabriella Rosanna Musillo
- Edijs Vavers
- Rosaria Piscitelli
Institutions
- Leipzig University of Applied Sciences (DE)
- Universidade de Santiago de Compostela (ES)
- Saxon Institute for Applied Biotechnology (DE)
- University of Bari Aldo Moro (IT)
- University of Tartu (EE)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c02423
- Primary Topic
- Pharmacological Receptor Mechanisms and Effects
- Type
- article
- Field-Weighted Citation Impact
- 0.00