1. Structure-Activity Relationships within a Series of σ 1 and σ 2 Receptor Ligands: Identification of a σ 2 Receptor Agonist (BS148) with Selective Toxicity against Metastatic Melanoma.
- Author
-
Franchini S, Sorbi C, Battisti UM, Tait A, Bencheva LI, Cichero E, Fossa P, Cilia A, Prezzavento O, Ronsisvalle S, Aricò G, Benassi L, Vaschieri C, Azzoni P, Magnoni C, and Brasili L
- Subjects
- Analgesics, Opioid chemical synthesis, Analgesics, Opioid chemistry, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Death drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Ligands, Male, Melanoma pathology, Mice, Models, Molecular, Molecular Structure, Piperidines chemical synthesis, Piperidines chemistry, Spiro Compounds chemical synthesis, Spiro Compounds chemistry, Structure-Activity Relationship, Analgesics, Opioid pharmacology, Antineoplastic Agents pharmacology, Melanoma drug therapy, Piperidines pharmacology, Receptors, sigma agonists, Spiro Compounds pharmacology
- 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 σ
1 R; three compounds were shown to be σ1 R agonists, while another proved to be the only σ1 R antagonist. Only one of the σ1 R agonists (BS148) also exhibited σ2 R 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 σ2 R 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 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2017
- Full Text
- View/download PDF