Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as

4-PPBP 4-PPBP is a molecule which binds to sigma receptors. 4-PPBP decreases neuronal nitric oxide synthase (nNOS) activity and ischemia-evoked nitric oxide (NO) production. 4-PPBP provides neuroprotection; this involves the prevention of ischemia-ind ...

(4-phenyl-1-(4-phenylbutyl) piperidine),

SA 4503 Cutamesine (SA 4503) is a synthetic sigma receptor agonist which is selective for the ''σ''1 receptor, a chaperone protein mainly found in the endoplasmic reticulum of cells in the central nervous system. These ''σ''1 receptors play a key role i ...

(cutamesine),

ditolylguanidine Ditolylguanidine is a sigma receptor agonist. It is somewhat selective for sigma receptors, but non-selective between the two sigma receptor subtypes, binding to both σ1 and σ2 with equal affinity. It has neuroprotective and antidepressant eff ...

, dimethyltryptamine, and

siramesine Siramesine (or Lu 28-179) is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects. It was developed by the pharmaceutical company H Lundbeck for th ...

. 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 A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be c ...

as sigma-1. Both localize to the

ER membrane The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

, although sigma-1 is also reported to be a cell surface receptor. Sigma-2 is an EXPREA domain protein (citation needed) with a mostly intracellular (ER membrane) localization.

Classification

Because the σ-receptor was originally discovered to be agonized by

benzomorphan Benzomorphan is a chemical compound that is the base for a series of drugs which variably act on the opioid kappa and sigma receptors, including the following compounds: * 5,9-DEHB * 8-CAC * Alazocine * Anazocine * Bremazocine * Butinazocine ...

opioids Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

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 Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...

, dextromethorphan, and

berberine Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), ''Berberis aristata'' (tree turmeric), ''Mahonia aquifolium'' (Oregon grape), ''Hydra ...

. 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 The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

. 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 Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

. 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 Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs. Normally, as ...

. 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. In 2007 selective σ-receptor agonists were shown to produce

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

-like effects in mice.

Ligands

Agonists

* Choline: *

3-MeO-PCP 3-Methoxyphencyclidine (3-MeO-PCP) is a dissociative hallucinogen of the arylcyclohexylamine class related to phencyclidine (PCP) which has been sold online as a designer drug. It acts mainly as an NMDA receptor antagonist, though it has also bee ...

: selective for σ₁ subtype, Ki = 42nM *

* Afobazole: selective for σ₁ subtype *

Allylnormetazocine Alazocine (developmental code name -10047), also known more commonly as ''N''-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activ ...

(SKF-10047) *

Anavex 2-73 Blarcamesine (development code ANAVEX2-73) is an experimental drug developed by Anavex Life Sciences. It is in phase IIb/phase III trials for Alzheimer's disease and Rett syndrome, phase IIa trials for Parkinson's disease, phase I trials for ep ...

Arketamine Arketamine (developmental code names PCN-101, HR-071603), also known as (''R'')-ketamine or (''R'')-(−)-ketamine, is the (''R'')-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the ''S''(+) enantiomer of ke ...

BD1031 BD1031 or (R)-2- -(3,4-dichlorophenyl)ethylctahydropyrrolo ,2-ayrazine is a selective sigma receptor agonist, with a reported binding affinity of ''K''i = 1 ± 0.2 nM for the sigma-1 receptor and 80 times selectivity over the sigma-2 receptor. Th ...

: selective for σ₁ subtype * BD1052: selective for σ₁ subtype *

Berberine Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), ''Berberis aristata'' (tree turmeric), ''Mahonia aquifolium'' (Oregon grape), ''Hydra ...

* Citalopram * Cocaine * Dehydroepiandrosterone (DHEA) * Dehydroepiandrosterone sulfate (DHEA-S) * Dextromethorphan (DXM): relatively selective for σ₁ subtype * Dextrorphan * ''N'',''N''-Dimethyltryptamine (DMT) *

Dimemorfan Dimemorfan (INN) (or dimemorphan) (brand names Astomin, Dastosirr, Tusben), or dimemorfan phosphate (JAN), also known as 3,17-dimethylmorphinan, is an antitussive (cough suppressant) of the morphinan family that is widely used in Japan and is als ...

Ditolylguanidine Ditolylguanidine is a sigma receptor agonist. It is somewhat selective for sigma receptors, but non-selective between the two sigma receptor subtypes, binding to both σ1 and σ2 with equal affinity. It has neuroprotective and antidepressant eff ...

* Escitalopram *

Fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...

* Fluvoxamine * Igmesine * Ketamine *

L-687,384 L-687,384 is a sigma receptor agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, a ...

: selective for σ₁ subtype *

Lamotrigine Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut synd ...

* Memantine: selective for σ₁ subtype, low affinity *

Methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...

* Methylphenidate * Noscapine * OPC-14523 * Opipramol *

PB-28 PB-28 is an agonist of the sigma-2 receptor The sigma-2 receptor (σ2R) is a sigma receptor subtype that has attracted attention due to its involvement in diseases such as cancer and neurological diseases. It is currently under investigation fo ...

: selective for σ₂ subtype *

Pentazocine Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such it is called an ...

* Pentoxyverine: selective for σ₁ subtype * Phencyclidine * (+)-3-PPP *

PRE-084 PRE-084 is a sigma receptor agonist, selective for the σ1 subtype. It has nootropic and antidepressant actions in animal studies, as well as antitussive and reinforcing effects. PRE-084 increases the expression of GDNF Glial cell line-der ...

: selective for σ₁ subtype * Pregnenolone *

Pregnenolone sulfate Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects. Biological activity Pre ...

: selective for σ₁ subtype *

Siramesine Siramesine (or Lu 28-179) is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects. It was developed by the pharmaceutical company H Lundbeck for th ...

UMB23 UMB may refer to: Universities * University of Manitoba, a university in Winnipeg, Manitoba, Canada * Marc Bloch University, also known as ''Université Marc Bloch'' (UMB), a university in France * Norwegian University of Life Sciences (NMBU), a ...

* UMB82

Antagonists

AC927 AC927 or 1-(2-phenylethyl)piperidine is a selective sigma receptor antagonist, with reported binding affinity of ''K''i = 30 ± 2 nM for the sigma-1 receptor and ''K''i = 138 ± 18 nM for the sigma-2 receptor, and negligible binding affinity for ...

* AHD1 * AZ66 *

BD1008 BD1008 or N- -(3,4-dichlorophenyl)ethylN-methyl-1-pyrrolidineethanamine is a selective sigma receptor antagonist, with a reported binding affinity of ''K''i = 2 ± 1 nM for the sigma-1 receptor and 4 times selectivity over the sigma-2 receptor. ...

BD-1047 BD-1047 is a sigma receptor antagonist, selective for the σ1 subtype. It has effects in animal studies suggestive of antipsychotic activity and may also be useful in the treatment of neuropathic pain. More recent studies also suggest a novel r ...

: selective for σ₁ subtype *

BD1060 BD1060 or ''N''- -(3,4-dichlorophenyl)ethyl1-pyrrolidineethanamine is a selective sigma receptor antagonist, with a reported binding affinity of ''K''i = 3 ± 0.1 nM for the sigma-1 receptor and greater than 50 times selectivity over the sigma-2 ...

: selective for σ₁ subtype *

BD1063 BD1063 or 1- -(3,4-dichlorophenyl)ethyl4-methylpiperazine is a selective sigma receptor antagonist, with a reported binding affinity of ''K''i = 9 ± 1 nM for the sigma-1 receptor and more than 49 times selectivity over the sigma-2 receptor. Co ...

: selective for σ₁ subtype *

BD1067 BD1067 or ''N''- -(3,4-dichlorophenyl)ethylN-ethyl-1-pyrrolidineethanamine is a selective sigma receptor antagonist, with a reported binding affinity of ''K''i = 2 ± 0.5 nM for the sigma-1 receptor and greater than 19 times selectivity over the ...

* BMY-14802 *

CM156 CM156 is a piperazine based chemical compound with nanomolar affinity for both sigma receptor subtypes that has been shown to counteract the deleterious effects of administered cocaine. See also * 3C-PEP 1-(3-Chlorophenyl)-4-(2-phenyleth ...

: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo hiazole-2(3H)-thione * E-5842 * Haloperidol *

LR132 LR132 or (+)-3,4-dichloro-N- 1R,2S)-2-(1-pyrrolidinyl)cyclohexylenzeneethanamine is a selective sigma receptor antagonist, with a reported binding affinity of ''K''i = 2 ± 0.1 nM for the sigma-1 receptor and more than 350 times selectivity over ...

: selective for σ₁ subtype * LR172 *

MS-377 MS-377 is a selective antagonist of the sigma-1 receptor. It possesses anti-psychotic properties. Properties MS-377 acts selectively at the sigma-1 receptor as an antagonist. It does not act on dopamine or serotonin receptors unlike most anti-p ...

: selective for σ₁ subtype * NE-100: selective for σ₁ subtype *

Panamesine Panamesine (; developmental code name EMD-57455) is a sigma receptor antagonist that was under development by Merck as a potential antipsychotic for the treatment of schizophrenia in the 1990s but was never marketed. It is a selective antagonist ...

* Phenothiazines *

Progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

* Rimcazole * S1RA (E-52862): selective for σ₁ subtype * Sertraline * UMB100 * UMB101 * UMB103 * UMB116 * YZ-011 * YZ-069 * YZ-185

References

External links

* {{Sigma receptor modulators Receptors