Sigma receptor

Schematic σ receptor

The sigma receptors σ₁ and σ₂ bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.

Classification

Sigma receptors were once thought to be a type of opioid receptor, because the d stereoisomers of the benzomorphan class of opioid drugs had no effects at μ, κ, and δ receptors, but reduced coughing.

However, pharmacological testing indicated that the sigma 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 these 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.

Function

The function of these receptors is poorly understood though an endogenous ligand, dimethyltryptamine, was found to interact with sigma-1. Activation of sigma 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 sigma agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and the herbal antidepressant berberine. However the exact role of sigma receptors is difficult to establish as many sigma agonists also bind to other targets such as the κ-opioid receptor and the NMDA receptor. In animal experiments, sigma antagonists such as rimcazole were able to block convulsions from cocaine overdose. Sigma antagonists are also under investigation for use as antipsychotic medications.

Physiologic effects

Physiologic effects when the sigma receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, and mydriasis. Some sigma receptor agonists—such as cocaine, a weak sigma agonist—exert convulsant effects in animals. Behavioral reactions to sigma agonists are rather heterogeneous: some individuals find sigma receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety.^{[citation needed]}

Recently selective σ–receptor agonists were shown to produce antidepressant effects in mice.

Ligands

Agonists

• 4-PPBP
• Afobazole: selective for σ₁ subtype
• Allylnormetazocine (SKF-10047)
• Amphetamine
• Citalopram
• Cocaine
• Dextromethorphan
• Dextrorphan
• Dimethyltryptamine
• Dimemorfan
• Ditolylguanidine
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Igmesine
• L-687,384: selective for σ₁ subtype
• Lamotrigine - Anticonvulsant, Bipolar Prophylaxis
• Methamphetamine
• Morphine/Heroin
• Noscapine^{[citation needed]}
• Opioids (Oxycodone, fentanyl, etc
• Opipramol
• Pentazocine: especially the "unnatural" enantiomer (+)-pentazocine, which lacks affinity for opioid receptors and so is a selective sigma agonist
• Pentoxyverine: selective for σ₁ subtype
• Phencyclidine
• PB-28: selective for σ₂ subtype
• PRE-084: selective for σ₁ subtype
• SA 4503
• Sertraline
• Siramesine

Antagonists

• BD-1008
• BD-1047: selective σ₁ antagonist
• BD-1063
• BMY-14802
• CM156: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione
• Haloperidol
• Rimcazole

External links

• MeSH sigma+Receptor