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.
Highlights
Sigma receptors, initially classified as an additional class of opioid receptors,[1] are nowadays considered a unique entity with no homology to opioid receptors or other mammalian proteins.[2]
16a (BS148) exhibited σ2R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines, whilst not affecting normal human melanocytes
We recently reported a new series of conformationally restricted spiro-dioxolane among which 1a and 1b showed high affinity and good selectivity for σ1R, behaving as σ1R agonists (Figure 1).[39]
Summary
Sigma receptors (σRs), initially classified as an additional class of opioid receptors,[1] are nowadays considered a unique entity with no homology to opioid receptors or other mammalian proteins.[2]. These results are consistent with an agonistic behavior of these compounds at 1 receptors, confirming results previously reported with 1b on a rat preparation.[39] In contrast, pre-treatment with 16b at 1.0 mg/kg s.c., followed by morphine injection (4.0 mg/kg s.c.) caused an increase in the opioid analgesic effect and the MAUC value was significantly higher than that of mice receiving morphine alone (192.4% with respect to 117.3%) (#p
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