Siramesine | Selective sigma-2 agonist

Siramesine (Lu 28-179, 147817-50-3) is a σ2 selective agonist (IC₅₀’s: σ1 = 17nM, σ2 = 0.2nM).¹ It produced non-sedating potent and long-last anxiolytic effects in rodents.² Siramesine induced caspase-independent programmed cell death in various cancer cell lines via increased levels of ROS and lysosomal leakage.^3,4,5 Mitochondrial destabilization via loss of membrane potential and increased ROS has also been offered as a mechanism of action for the triggering of cell death by Siramesine.⁶

References/Citations:

1) Perregaard et al. (1995), Sigma ligands with subnanomolar affinity and preference for the sigma 2 binding site. 1. 3-(omega-aminoalkyl)-1H-indoles; J. Med. Chem. 38 1998
2) Sanchez et al. (1997), The selective sigma2-ligand Lu 280179 has potent anxiolytic effects in rodents; J. Pharmacol. Exp. Ther. 283 1323
3) Ostenfeld et al. (2005), Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress; Cancer Res. 65 8975
4) Ostenfeld et al. (2008), Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation; Autophagy 4 487
5) Dielschneider et al. (2016), Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism; Leukemia 30 1290
6) Cesen et al. (2013), Siramesine triggers cell death through destabilization of mitochondria, but not lysosomes; Cell Death Dis. 4 e818