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 sigma receptor (sigma R) ligands were prepared and studied. Most were found to have a high affinity and selectivity for sigma R-1; three compounds were shown to be sigma R-1 agonists, while another proved to be the only sigma R-1 antagonist. Only one of the sigma R-1 agonists (BS148) also exhibited sigma R-2 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 sigma R-2 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.