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

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 R; three compounds were shown to be σ R agonists, while another proved to be the only σ R antagonist. Only one of the σ R agonists (BS148) also exhibited σ 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 σ 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.