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

  • ChemMedChem. 2017 Nov 22;12(22):1893-1905. doi: 10.1002/cmdc.201700427.
Silvia Franchini  1 ,  Claudia Sorbi  1 ,  Umberto Maria Battisti  1 ,  Annalisa Tait  1 ,  Leda Ivanova Bencheva  1 ,  Elena Cichero  2 ,  Paola Fossa  2 ,  Antonio Cilia  3 ,  Orazio Prezzavento  4 ,  Simone Ronsisvalle  4 ,  Giuseppina Aricò  4 ,  Luisa Benassi  5 ,  Cristina Vaschieri  5 ,  Paola Azzoni  5 ,  Cristina Magnoni  5 ,  Livio Brasili  1
Affiliations
  • 1. Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
  • 2. Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16132, Genova, Italy.
  • 3. Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148, Milano, Italy.
  • 4. Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale Andrea Doria 6, 95125, Catania, Italy.
  • 5. Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa, Università degli Studi di Modena e Reggio Emilia, via del Pozzo 71, 41124, Modena, Italy.
PMID: 28940806 DOI: 10.1002/cmdc.201700427
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 σ1 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.

Keywords
SK-MEL-2 cells; analgesia; antiproliferative activity; melanoma; sigma receptors.
Products