Lu 28-179

Siramesine (Lu 28-179) fumarate is a potent sigma-2 receptor agonist. Siramesine fumarate has a subnanomolar affinity for sigma-2 receptors (IC50=0.12?nM) and exhibits a 140-fold selectivity for sigma-2 receptors over sigma-1 receptors (IC50=17?nM). Siramesine fumarate triggers cell death through destabilisation of mitochondria, but not lysosomes. Anti-cancer activity[1][2][3].

Siramesine is a blood-brain barrier penetrant, selective and potent sigma-2 receptor agonist, which exhibits potent and very long-lasting anxiolytic effects in rodents. Also, siramesine is a lysosome-destabilizing agent that causes lysosomal cell death in varies immortalized and cancer cell lines.

[1] Perregaard J, et al. Sigma ligands with subnanomolar affinity and preference for the sigma 2 binding site. 1. 3-(omega-aminoalkyl)-1H-indoles. J Med Chem. 1995;38(11):1998-2008. DOI:10.1021/jm00011a019
[2] ?esen MH, et al. Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Cell Death Dis. 2013;4(10):e818. Published 2013 Oct 3. DOI:10.1038/cddis.2013.361
[3] Ostenfeld MS, et al. Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy. 2008;4(4):487-499. DOI:10.4161/auto.5774