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. Some early literature proposed a third subtype ("sigma-3") based on phenylaminotetralin (PAT) ligands, but later work showed this binding corresponded to the histamine H1 receptor; "sigma-3" is not recognized in current nomenclature.

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 EXPERA 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. Putative sigma-3 receptor In the early 1990s, a "sigma-3" binding site was proposed based on phenylaminotetralin (PAT) ligands and functional assays that linked PAT binding to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. Subsequent pharmacological and radioligand-binding studies demonstrated that these so-called sigma-3 sites correspond to histamine H1 receptors rather than a distinct sigma receptor subtype. As a result, contemporary classifications recognize only sigma-1 and sigma-2 receptors.

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. Early rodent studies reported that σ-receptor ligands can functionally antagonize opioid analgesia: (+)-pentazocine and 1,3-di(2-tolyl)guanidine reduced morphine analgesia in a haloperidol-reversible, D2-independent manner, consistent with a tonically active anti-opioid σ1 system.

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, dimethyltryptamine (DMT), 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.

In mice, σ1 activation attenuated μ-, κ-, and δ-opioid analgesia without altering morphine's effects on gastrointestinal transit or lethality, while σ blockade with haloperidol enhanced analgesia and eliminated strain differences in κ-agonist sensitivity.

Ligands Agonists

Choline 3-MeO-PCP: selective for σ1 subtype, Ki = 42nM 4-PPBP Afobazole: selective for σ1 subtype Allylnormetazocine (SKF-10047) Amantadine Amitriptyline 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 Dimethyltryptamine (DMT) Dimemorfan Ditolylguanidine Escitalopram Fluoxetine Fluvoxamine Igmesine Ketamine L-687,384: selective for σ1 subtype (& Spipethiane).

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)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 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

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