A new series of spirocyclic σ receptor (σR) ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ1R; three compounds were shown to be σ1R agonists, while another proved to be the only σ1R antagonist. Only one of the σ1R agonists (BS148) also exhibited σ2R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines without affecting normal human melanocytes. The antiproliferative activity of this compound suggested an σ2R agonist profile. Further, preliminary investigations indicated that the mechanism of metastatic malignant melanoma cell death induced by BS148 is due, at least in part, to apoptosis.

Structure-Activity Relationships within a Series of σ1 and σ2 Receptor Ligands: Identification of a σ2 Receptor Agonist (BS148) with Selective Toxicity against Metastatic Melanoma

Franchini, Silvia;Prezzavento, Orazio;Ronsisvalle, Simone;
2017-01-01

Abstract

A new series of spirocyclic σ receptor (σR) ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ1R; three compounds were shown to be σ1R agonists, while another proved to be the only σ1R antagonist. Only one of the σ1R agonists (BS148) also exhibited σ2R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines without affecting normal human melanocytes. The antiproliferative activity of this compound suggested an σ2R agonist profile. Further, preliminary investigations indicated that the mechanism of metastatic malignant melanoma cell death induced by BS148 is due, at least in part, to apoptosis.
2017
analgesia; antiproliferative activity; melanoma; sigma receptors; SK-MEL-2 cells; Analgesics, Opioid; Animals; Antineoplastic Agents; Cell Death; Cell Proliferation; Cell Survival; Cells, Cultured; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Ligands; Male; Melanoma; Mice; Models, Molecular; Molecular Structure; Piperidines; Receptors, sigma; Spiro Compounds; Structure-Activity Relationship; Molecular Medicine; Pharmacology, Toxicology and Pharmaceutics (all); Organic Chemistry
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/314865
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