σ–receptors were once thought to be a type of opioid receptor, because the d- stereoisomers of the benzomorphan class of opioid drugs reduced coughing, as do some other opioid derivatives such as dextromethorphan. However, such drugs had no effects at μ (Mu), κ (kappa), or δ (Delta) receptors.
However, pharmacological testing indicated that the σ-receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. For example, phencyclidine (PCP), and the antipsychotic haloperidol may interact with σ-receptors. Neither phencyclidine nor haloperidol have any appreciable chemical similarity to the opioids.
When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors. At this point, they were designated as a separate class of receptors.
The function of these receptors is poorly understood though an endogenous ligand, dimethyltryptamine, was found to interact with σ1. Activation of σ–receptors by an agonist ligand may induce hallucinogenic effects and also may be responsible for the paradoxical convulsions sometimes seen in opiate overdose. Drugs known to be σ–agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and the herbal antidepressant berberine. However the exact role of σ–receptors is difficult to establish as many σ–agonists also bind to other targets such as the κ-opioid receptor and the NMDA glutamate receptor. In animal experiments, σ–antagonists such as rimcazole were able to block convulsions from cocaine overdose. σ–antagonists are also under investigation for use as antipsychotic medications.
Physiologic effects when the σ–receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, and mydriasis. Some σ–receptor agonists—such as cocaine, a weak σ–agonist—exert convulsant effects in animals. Behavioral reactions to σ–agonists are rather heterogeneous: some individuals find σ–receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety.
- Afobazole: selective for σ1 subtype
- Allylnormetazocine (SKF-10047)
- BD1031: selective for σ1 subtype
- BD1052: selective for σ1 subtype
- Dehydroepiandrosterone (DHEA)
- Dehydroepiandrosterone sulfate (DHEA-S)
- N,N-Dimethyltryptamine (DMT)
- L-687,384: selective for σ1 subtype
- Opioids (Oxycodone, fentanyl, etc.)
- PB-28: selective for σ2 subtype
- Pentazocine: especially the "unnatural" enantiomer (+)-pentazocine, which lacks affinity for opioid receptors and so is a selective σ–agonist
- Pentoxyverine: selective for σ1 subtype
- PRE-084: selective for σ1 subtype
- Pregnenolone sulfate
- SA 4503: selective for σ1 subtype
- BD-1047: selective for σ1 subtype
- BD1060: selective for σ1 subtype
- BD1063: selective for σ1 subtype
- CM156: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione
- LR132: selective for σ1 subtype
- MS-377: selective for σ1 subtype
- NE-100: selective for σ1 subtype
- S1RA (E-52862): selective for σ1 subtype
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- sigma Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)