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

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 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.

Novel Dithiolane-Based Ligands Combining Sigma and NMDA Receptor Interactions as Potential Neuroprotective Agents

“…This is consistent with a S1R agonist activity. 14 However, for NMDA induced toxicity, PB212 did not completely abolish the neuroprotective capacity of III, suggesting that its effect could be mediated by an either direct or indirect modulation of the NMDA receptor. Interestingly, compounds bearing the 4benzylpiperazine basic moiety (I, II, and 11) displayed strong…”

“…They behave as S1R agonists, with I and II showing high affinity for S1R (K i = 0.74 and 1.3 nM, respectively) and moderate affinity for S2R subtype (S1R/S2R selectivity: 47 and 72, respectively), whereas compound III showed a low nanomolar affinity against both SR subtypes (K i S1R= 12 nM and K i S2R = 5.0 nM). 14 Molecular docking studies highlighted that a salt bridge between the protonated nitrogen atom of the benzylpiperazine/piperidine moiety and Glu172 is essential for the binding to S1R. 16,17 The nature of the pharmacophoric amine (benzylpiperidine or benzylpiperazine) guided the binding mode within the S1R binding site.…”

“…derivatives (i.e., I and II) positioned the spirocyclic moiety in the primary hydrophobic pocket delimitated by Met93, Tyr103, Ile 178, and Ala 185, the piperidine derivatives (i.e., III) exhibited a reverse docking mode with the benzyl moiety into the primary pocket (Figure 1A and Figure SI-1A). 14 To better investigate the structure activity relationships (SAR) of this SRs ligand series, herein we expanded the library by combining the pharmacophoric amines with dithiolane rings and their bioisosters. Considering the binding mode of compound III at S1R, 17 novel analogues were prepared modifying the spirocyclic moiety (Figure 1B) and aiming to clarify the steric and electrostatic properties necessary for strong interactions within the secondary hydrophobic pocket (compounds 1−9, Table 1).…”

“…This strategy was successfully applied to haloperidol-constrained SR ligands providing compounds with enhanced affinity and selectivity for the S2R subtype. 14 In addition the structural simplification of the spiro-portion was investigated in both benzylpiperazine and benzylpiperidine series (compounds 8−11). The corresponding dioxolane bioisosters (12 and 13) were also prepared.…”

“…A partnership between S1Rs and NMDA receptors leading to beneficial outcomes in neurodegeneration has been demonstrated . Over the last 10 years, our group has developed an extensive library of SR modulators combining different substituted five-membered heterocyclic rings with a broad range of amines (i.e., benzylpiperidine and benzylpiperazine). − Among the previously synthesized compounds, I–III (Table ) were of particular interest. They behave as S1R agonists, with I and II showing high affinity for S1R ( K i = 0.74 and 1.3 nM, respectively) and moderate affinity for S2R subtype (S1R/S2R selectivity: 47 and 72, respectively), whereas compound III showed a low nanomolar affinity against both SR subtypes ( K i S1R= 12 nM and K i S2R = 5.0 nM) .…”