Structure-Activity Relationships within a Series of sigma1 and sigma2 Receptor Ligands: Identification of a sigma2 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 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.