Sigma receptor
Encyclopedia
The sigma receptors σ1
and σ2
bind to ligands such as 4-PPBP
, SA 4503
, ditolylguanidine
, dimethyltryptamine
and siramesine
.
, 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.
, 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, 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.
, 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.
Recently selective σ–receptor agonists were shown to produce antidepressant
effects in mice.
Sigma-1 receptor
The sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene....
and σ2
Sigma-2 receptor
The sigma-2 receptor is a sigma receptor which preferentially binds to siramesine and PB28. Unlike sigma-1 receptor, it has not yet been cloned.Activation of the receptor can cause apoptosis...
bind to ligands such as 4-PPBP
4-PPBP
4-PPBP is a molecule which binds to sigma receptors....
, SA 4503
SA 4503
SA 4503 is a sigma receptor agonist....
, ditolylguanidine
Ditolylguanidine
Ditolylguanidine is a sigma receptor agonist. It is 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 effects, and potentiates the effects of NMDA antagonists....
, dimethyltryptamine
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
and siramesine
Siramesine
Siramesine is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects...
.
Classification
Sigma receptors were once thought to be a type of opioid receptorOpioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
, because the d stereoisomers of the benzomorphan
Benzomorphan
Benzomorphan is a chemical compound.It is the base for a series of drugs which variably act on the opioid and sigma receptors, including, but not limited to, the following compounds:...
class of opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
drugs had no effects at μ
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
, κ
Kappa Opioid receptor
The κ-opioid receptor is a protein that in humans is encoded by the OPRK1 gene. The κ-opioid receptor is one of five related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds...
, and δ
Delta Opioid receptor
The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as its endogenous ligands.-Function:...
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
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
(PCP), and the antipsychotic haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
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, dimethyltryptamineDimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
, was found to interact with sigma-1. Activation of sigma receptors by an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
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
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
/diacetylmorphine, PCP
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
, fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
, methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
, dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
, and the herbal antidepressant berberine
Berberine
Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary...
. 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
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
. In animal experiments, sigma antagonists such as rimcazole
Rimcazole
Rimcazole is an antagonist of the sigma receptor as well as a dopamine reuptake inhibitor. Sigma receptors are thought to be involved in the drug psychosis that can be induced by some drugs such as PCP and cocaine, and rimcazole was originally researched as a potential antipsychotic with a...
were able to block convulsions from cocaine overdose. Sigma antagonists are also under investigation for use as antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
medications.
Physiologic effects
Physiologic effects when the sigma receptor is activated include hypertoniaHypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, tachypnea
Tachypnea
Tachypnea means rapid breathing. Any rate between 12-20 breaths per minute is normal. Tachypnea is a respiration rate greater than 20 breaths per minute. - Distinction from other breathing terms :...
, antitussive effects, and mydriasis
Mydriasis
Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
. 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
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
and often report feelings of malaise or anxiety.
Recently selective σ–receptor agonists were shown to produce antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
effects in mice.
Agonists
- 4-PPBP4-PPBP4-PPBP is a molecule which binds to sigma receptors....
- AfobazoleAfobazoleAfobazole is an anxiolytic drug launched in Russia in the early 2000s. It produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions, making it more selective in action than many currently used drugs for this application...
: selective for σ1 subtype - AllylnormetazocineAllylnormetazocineAlazocine , or -N-allylnormetazocine , was the first drug discovered to act as a σ1 receptor agonist . It has no significant affinity for the σ2 receptor. Alazocine also acts as a κ-opioid receptor agonist , and to a much lesser extent, as an NMDA receptor antagonist ....
(SKF-10047) - AmphetamineAmphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
- CitalopramCitalopramCitalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
- CocaineCocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
- DextromethorphanDextromethorphanDextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
- DextrorphanDextrorphanDextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextro-stereoisomer of racemorphan, the levo-half being levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6...
- DimethyltryptamineDimethyltryptamineN,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
- DimemorfanDimemorfanDimemorfan is an antitussive or cough suppressant which acts as a sigma receptor agonist. It is an analogue of dextromethorphan and dextrorphan, but lacks significant NMDA receptor antagonistic action and dissociative effects, thereby having reduced abuse potential and adverse effects in comparison....
- DitolylguanidineDitolylguanidineDitolylguanidine is a sigma receptor agonist. It is 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 effects, and potentiates the effects of NMDA antagonists....
- EscitalopramEscitalopramEscitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
- FluoxetineFluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
- FluvoxamineFluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
- IgmesineIgmesineIgmesine is a sigma receptor agonist. It has neuroprotective and antidepressant effects in animal studies, as well as nootropic effects in models of age related cognitive decline...
- L-687,384L-687,384L-687,384 is a sigma receptor agonist, selective for the σ1 subtype, as well as an NMDA antagonist....
: selective for σ1 subtype - LamotrigineLamotrigineLamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
- Anticonvulsant, Bipolar Prophylaxis - MethamphetamineMethamphetamineMethamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
- MorphineMorphineMorphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
/Heroin - NoscapineNoscapineNoscapine is a benzylisoquinoline alkaloid from plants of the Papaveraceae family, without significant painkilling properties. This agent is primarily used for its antitussive effects. It has also been shown to have anticancer activity...
- Opioids (OxycodoneOxycodoneOxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...
, fentanyl, etc - OpipramolOpipramolOpipramol is an antidepressant and anxiolytic used in Germany and other European countries. Although it is a member of the tricyclic antidepressants, opipramol's primary mechanism of action is much different in comparison...
- PentazocinePentazocinePentazocine is a synthetically prepared prototypical mixed agonist-antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain...
: especially the "unnatural" enantiomer (+)-pentazocine, which lacks affinity for opioid receptors and so is a selective sigma agonist - PentoxyverinePentoxyverinePentoxyverine or carbetapentane is an antitussive commonly used for cough associated with illnesses like common cold. It is sold over-the-counter in the United States as Solotuss, or in combination with other medications, especially decongestants...
: selective for σ1 subtype - PhencyclidinePhencyclidinePhencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
- PB-28: selective for σ2 subtype
- PRE-084PRE-084PRE-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....
: selective for σ1 subtype - SA 4503SA 4503SA 4503 is a sigma receptor agonist....
- SertralineSertralineSertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
- SiramesineSiramesineSiramesine is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects...
Antagonists
- BD-1008BD-1008BD-1008 is a sigma receptor antagonist, which blocks the effects of cocaine in animal studies, and may be potentially useful in the development of antidotes for the treatment of cocaine overdose....
- BD-1047BD-1047BD-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....
: selective σ1 antagonist - BD-1063BD-1063BD-1063 is a sigma receptor antagonist, with moderate selectivity for the σ1 subtype. It blocks the effects of MDMA in animal studies, and reduces alcohol intake in animal models of alcoholism....
- BMY-14802BMY-14802BMY-14802 is a drug with antipsychotic effects, which acts as both a sigma receptor antagonist, and a 5-HT1A agonist....
- CM156: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione
- HaloperidolHaloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
- RimcazoleRimcazoleRimcazole is an antagonist of the sigma receptor as well as a dopamine reuptake inhibitor. Sigma receptors are thought to be involved in the drug psychosis that can be induced by some drugs such as PCP and cocaine, and rimcazole was originally researched as a potential antipsychotic with a...