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Sigma receptors (σ-receptors) are protein receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 receptors (σ₁) and sigma-2 receptors (σ₂), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.

The fungal protein ERG2, a C-8 sterol isomerase, falls into the same protein family as sigma-1. Both localize to the ER membrane, although sigma-1 is also reported to be a cell surface receptor. Sigma-2 is an EXPREA domain protein with a mostly intracellular (ER membrane) localization.

Classification

Because the σ-receptor was originally discovered to be agonized by benzomorphan opioids and antagonized by naltrexone, σ-receptors were originally believed to be a type of opioid receptor. When the σ₁ receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors, but rather showed similarity to fungal proteins involved in sterol synthesis. At this point, they were designated as a separate class of proteins.

Function

The function of these receptors is poorly understood. Drugs known to be σ-agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and 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.

The abundant neurosteroid steroid hormone DHEA is an agonist at sigma receptors and along with pregnenolone could be endogenous agonist ligands; opposed by sigma antagonistic activity from progesterone. Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ₁.

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.

In 2007, selective σ-receptor agonists were shown to produce antidepressant-like effects in mice.

σ-receptors were also shown to have a role in the regulation of iron/heme homeostasis.

Ligands

Agonists

• Choline
• 3-MeO-PCP: selective for σ₁ subtype, Ki = 42nM
• 4-PPBP
• Afobazole: selective for σ₁ subtype
• Allylnormetazocine (SKF-10047)
• Anavex 2-73
• 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 (& Spipethiane).
• Lamotrigine
• Memantine: selective for σ₁ subtype, low affinity
• Methamphetamine
• Methylphenidate
• Noscapine
• OPC-14523
• Opipramol
• PB-28: selective for σ₂ subtype
• Pentazocine
• Pentoxyverine: selective for σ₁ subtype
• Phencyclidine
• (+)-3-PPP
• PRE-084: selective for σ₁ subtype
• Pregnenolone
• Pregnenolone sulfate
• SA 4503: selective for σ₁ subtype
• Siramesine
• UMB23
• UMB82

Antagonists

• AC927
• AHD1
• AZ-66
• 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)benzothiazole-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
• Phenothiazines
• Progesterone
• Rimcazole
• S1RA (E-52862): selective for σ₁ subtype
• Sertraline
• UMB 98 & UMB 99
• UMB100
• UMB101
• UMB103
• UMB116
• YZ-011
• YZ-067
• YZ-069
• YZ-185

References

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External links

• sigma+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

• Receptors