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Siramesine came out of H. Lundbeck's sigma-receptor chemistry program in Denmark in the mid-1990s, and it is still one of the most selective sigma-2 ligands ever made, with subnanomolar affinity and roughly 140-fold preference for sigma-2 over sigma-1. It moved into human testing for anxiety and depression on the strength of strong anxiolytic- and antidepressant-like signals in rodent models. Lundbeck quietly shelved the psychiatric program in the mid-2000s without publishing a clear efficacy failure; the company's own statements pointed to commercial rather than safety reasons. The molecule did not disappear, though; oncology researchers picked it back up because at higher concentrations it destabilizes lysosomal membranes and kills tumor cells, giving siramesine a stranger second career than most abandoned psychiatric drugs get.
- anxiolytic-like effects in rodent behavioral models
- antidepressant-like effects in forced-swim and related assays
- well tolerated in early-phase human dosing
- remains the field's benchmark for defining the sigma-2 binding site
- at cancer-research doses it is directly cytotoxic via lysosomal disruption
- Siramesine's roughly 140-fold selectivity for sigma-2 over sigma-1 makes it the reference ligand pharmacologists still use to define the sigma-2 binding site.
Mechanism
Highly selective sigma-2 receptor (IC50 ~0.12 nM at sigma-2, ~140x less potent at sigma-1) with additional affinity at the transporter and receptor; at higher concentrations it permeabilizes lysosomal membranes, which is the basis of its use as a cancer-research tool.
Safetyrisks and cautions, not medical advice
Two very different exposure ranges hide inside this one molecule. At the low concentrations that produced anxiolytic effects it behaves like an ordinary receptor ligand; at the higher concentrations used in oncology work it ruptures lysosomal membranes, floods cells with reactive oxygen species and kills them by a caspase-independent route, and that effect is not confined to tumor cells. Lundbeck took it into Phase II for anxiety around 2000 and never published a trial result, so the human tolerability record is a blank. Lipid-soluble antioxidants blunt that cytotoxicity in culture, which is a laboratory observation and not a safeguard.
History
Synthesized and characterized by H. Lundbeck A/S starting around 1995; advanced into Phase I/II human trials for anxiety and depression in the early 2000s; the psychiatric development program was discontinued around 2004, and subsequent research interest shifted almost entirely to oncology.
Subjective profileweighing the evidence above
A textbook sigma-2 reference ligand that never became a psychiatric drug but found a second life as a cancer-research tool.
Resources
This entry is here for reference.
Research
- 1.Sigma ligands with subnanomolar affinity and preference for the sigma 2 binding site. 1. 3-(omega-aminoalkyl)-1H-indoles
- 2.The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Was siramesine ever approved as a psychiatric medication?
No. Lundbeck tested it in early-phase human trials for anxiety and depression but discontinued the program in the mid-2000s before it reached approval.
Why do cancer researchers still study siramesine?
At the concentrations used in oncology research, it disrupts lysosomal membranes inside tumor cells, a mechanism separate from its psychiatric sigma-2 activity that researchers now study for anticancer potential.
Limitations of the evidence
- limited public human safety data since the psychiatric program stopped early
Adverse effects
- at cancer-research doses it is directly cytotoxic via lysosomal disruption
Notes and cautions
- no long-term human tolerability record