Sigma-1 agonist
Sigma-1 receptor agonist
- Sigma-1 is an ER-membrane chaperone
- Regulates calcium signaling and protein trafficking
- May facilitate NMDA surface expression
- neuroprotective effects (preclinical evidence)
- potential relevance to mood disorders with glutamatergic dysregulation
- putative anti-inflammatory and antiviral effects
- considered a principal mechanism of Auvelity (depression) and Nuedexta (pseudobulbar affect)
- likely contributes to antiseizure mechanism
- Putative endogenous σ1 agonists: DMT, DHEA, pregnenolone
Drugs with this mechanism (9)
- Dextromethorphan — OTC cough suppressant; NMDA antagonist and sigma-1 agonist, dissociative in overdose.
- Dextrorphan — Active dextromethorphan metabolite; NMDA antagonism drives dissociation and abuse potential.
- Dehydroepiandrosterone — Adrenal precursor of testosterone and estradiol, and a sigma-1 agonist in the central nervous system.
- DHEAS — The sulfated, circulating reservoir form of DHEA; a negative modulator at GABA-A.
- N,N-dimethyltryptamine — Short-acting serotonergic psychedelic; active principle of ayahuasca.
- Fenfluramine — Serotonin releaser once in "fen-phen"; now for Dravet seizures, valvulopathy risk.
- Fluvoxamine — Sigma-1-active SSRI and strong CYP1A2 inhibitor; more GI upset than other SSRIs.
- Fluvoxamine CR — Controlled-release fluvoxamine for OCD and social anxiety; a potent CYP1A2 inhibitor.
- Pregnenolone — Precursor to every other steroid hormone; sigma-1 agonist, sold over the counter.
Self-check
- What kind of protein is sigma-1?
An ER-membrane chaperone. - What evidence level supports its neuroprotective effects here?
Preclinical.
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