Sigma-1: nootropics and compounds | sci-wiki

Opipramol

Opipramol is an anxiolytic and antidepressant medication that is structurally related to the tricyclic antidepressants but has a distinct mechanism, lacking their characteristic reuptake inhibition of serotonin and noradrenaline. Instead it acts chiefly as a high-affinity ligand at sigma-1 and sigma-2 receptors, with additional histamine H1 antagonism and weaker D2 and 5-HT2 blockade; preclinical work indicates that its sigma activity, including selective downregulation of sigma-2 sites, underlies its anxiolytic profile. In a placebo-controlled trial it produced anxiolytic efficacy comparable to alprazolam in generalized anxiety disorder, and it retains use chiefly for generalized anxiety and somatoform disorders. Marketed in Germany and other European countries since the 1960s under brand names such as Insidon, it continues to be studied for sigma-mediated actions, including experimental effects on drug-seeking behavior via the Rac1 pathway.

reference

Nootropic

Pregnenolone Sulfate

Pregnenolone sulfate (PregS) is an endogenous excitatory neurosteroid (a steroid synthesized in and acting upon the nervous system) formed by sulfation of pregnenolone at its 3beta-hydroxyl group. It is among the most intensively studied neurosteroids in ion-channel pharmacology, acting simultaneously as a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors that contain GluN2A or GluN2B subunits (the principal glutamate-gated channels underlying synaptic plasticity), a negative allosteric modulator of GABA-A receptors (the brain's main inhibitory chloride channels), a low-affinity agonist of the sigma-1 receptor (an intracellular chaperone protein) and the prototypical agonist of the TRPM3 cation channel. Through these convergent actions it enhances glutamatergic transmission, hippocampal acetylcholine release, long-term potentiation and memory consolidation in animal models, which underlies its reputation as a pro-cognitive neurosteroid. Its physiological concentrations, and even its unambiguous presence in mammalian brain, remain debated, so much of the evidence base derives from experimental administration rather than demonstrated endogenous signaling.

reference

Psychedelic

DMT

N,N-Dimethyltryptamine (DMT) is a naturally occurring tryptamine psychedelic that acts principally as an agonist at serotonin 5-HT2A receptors and is the main psychoactive constituent of the Amazonian brew ayahuasca. A distinguishing feature is that DMT also binds and regulates the sigma-1 receptor, an intracellular chaperone protein; this activity separates it mechanistically from the phenethylamine hallucinogens and has been linked in preclinical work to neuroprotective effects, including attenuation of spreading depolarization in ischemic brain. DMT is synthesized endogenously in mammalian tissue and behaves as a substrate for serotonin and vesicular monoamine transporters, though its physiological role remains debated. Smoked or injected, it produces an intense but brief altered state cleared within minutes, and controlled human studies have mapped its rapid autonomic, neuroendocrine, and subjective effects; continuous-infusion protocols now extend the experience and inform its investigation, including in fumarate salt form, as a rapid-acting treatment for depression.

reference