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

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. Receptive to new ideas: Development of new spirocyclic σ receptor (σR) ligands led to three compounds with σ1R agonist activity and one σ1R antagonist. One of the σ1R agonists exhibited selective toxicity toward metastatic melanoma cell lines, suggesting agonistic behavior at σ2R as well. Docking studies were performed on the theoretical σ1R homology model.