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

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 clinically relevant affinities for 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.

Function

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, fluoxetine, 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

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.

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

Ligands

Agonists

• 3-MeO-PCP: selective for σ₁ subtype, Ki = 42nM
• 4-PPBP
• Afobazole: selective for σ₁ subtype
• Allylnormetazocine (SKF-10047)
• Arketamine
• BD1031: selective for σ₁ subtype
• BD1052: selective for σ₁ subtype
• Berberine
• Citalopram
• Cocaine
• Dehydroepiandrosterone (DHEA)
• Dehydroepiandrosterone sulfate (DHEA-S)
• Dextromethorphan (DXM): relatively selective for σ₁ subtype
• Dextrorphan
• N,N-Dimethyltryptamine (DMT)
• Dimemorfan
• Ditolylguanidine
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Igmesine
• Ketamine
• L-687,384: selective for σ₁ subtype
• Lamotrigine
• Memantine: selective for σ₁ subtype, low affinity
• Methamphetamine
• Methoxetamine: selective for σ₁ subtype
• Methylphenidate
• Noscapine
• OPC-14523
• Some Opioids: (Buprenorphine, Pentazocine, Tapentadol, Tramadol, etc.)
• Opipramol
• PB-28: selective for σ₂ subtype
• Pentoxyverine: selective for σ₁ subtype
• Phencyclidine
• (+)-3-PPP
• PRE-084: selective for σ₁ subtype
• Pregnenolone
• Pregnenolone sulfate
• Quetiapine
• SA 4503: selective for σ₁ subtype
• Siramesine
• UMB23
• UMB82

Antagonists

• AC927
• AHD1
• AZ66
• BD1008
• BD-1047: selective for σ₁ subtype
• BD1060: selective for σ₁ subtype
• BD1063: selective for σ₁ subtype
• BD1067
• BMY-14802
• CM156: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione
• E-5842
• Haloperidol
• LR132: selective for σ₁ subtype
• LR172
• MS-377: selective for σ₁ subtype
• NE-100: selective for σ₁ subtype
• Panamesine
• Progesterone
• Rimcazole
• S1RA (E-52862): selective for σ₁ subtype
• Sertraline
• UMB100
• UMB101
• UMB103
• UMB116
• YZ-011
• YZ-069
• YZ-185

External links

• sigma Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)