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

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.