Sigma receptors (σ-receptors) are

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

s that bind

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

s such as 4-PPBP (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,

dimethyltryptamine ''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...

, and siramesine. There are two subtypes,

sigma-1 receptor The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the ''SIGMAR1'' gen ...

s (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 ...

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 (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 * Butinazoc ...

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 u ...

and antagonized by

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been foun ...

, 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 Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

diacetylmorphine Heroin, also known as diacetylmorphine and diamorphine among other names, is a potent opioid mainly used as a recreational drug for its euphoric effects. Medical grade diamorphine is used as a pure hydrochloride salt. Various white and brow ...

opipramol Opipramol, sold under the brand name Insidon among others, is an anxiolytic and antidepressant that is used throughout Europe. Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is no ...

, PCP,

fluvoxamine Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...

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. Methamp ...

dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with b ...

, 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), ''Hydras ...

. 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 The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind ...

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 rece ...

. In animal experiments, σ-antagonists such as

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 phencyclidine and cocaine, and rimcazole was o ...

were able to block convulsions from cocaine overdose. σ-antagonists are also under investigation for use as

antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...

medications. The abundant neurosteroid steroid hormone

DHEA Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functi ...

is an agonist at sigma receptors and along with

pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocor ...

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 majo ...

. 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 Hypertonia is a term sometimes used synonymously with spasticity and rigidity in the literature surrounding damage to the central nervous system, namely upper motor neuron lesions. Impaired ability of damaged motor neurons to regulate descending ...

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

tachypnea Tachypnea, also spelt tachypnoea, is a respiratory rate greater than normal, resulting in abnormally rapid and shallow breathing. In adult humans at rest, any respiratory rate of 1220 per minute is considered clinically normal, with tachypnea b ...

antitussive Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ...

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, a ...

. 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 Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...

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 effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...

-like effects in mice.

Ligands

Agonists

Choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...

: *

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 be ...

: selective for σ₁ subtype, Ki = 42nM * 4-PPBP * Afobazole: selective for σ₁ subtype * Allylnormetazocine (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 fo ...

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 k ...

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. T ...

: 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), ''Hydras ...

Citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and so ...

Cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...

* Dehydroepiandrosterone (DHEA) * Dehydroepiandrosterone sulfate (DHEA-S) *

Dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with b ...

(DXM): relatively selective for σ₁ subtype *

Dextrorphan Dextrorphan (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. D ...

* ''N'',''N''-Dimethyltryptamine (DMT) * Dimemorfan * Ditolylguanidine *

Escitalopram Escitalopram, sold under the brand names Lexapro and Cipralex, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder and generalized anxiet ...

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 diso ...

Fluvoxamine Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...

* Igmesine *

Ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppress ...

* L-687,384: 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 sy ...

Memantine Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...

: 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. Methamp ...

Methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...

Noscapine Noscapine (also known as Narcotine, Nectodon, Nospen, Anarcotine and (archaic) Opiane) is a benzylisoquinoline alkaloid, of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the family Papaveraceae ( ...

* OPC-14523 *

Opipramol Opipramol, sold under the brand name Insidon among others, is an anxiolytic and antidepressant that is used throughout Europe. Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is no ...

* PB-28: 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 Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percept ...

* (+)-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-deri ...

: selective for σ₁ subtype *

Pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocor ...

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 Pr ...

: selective for σ₁ subtype * Siramesine * UMB23 * 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 ...

* AHD1 * AZ66 *

BD1008 BD1008 or N- -(3,4-dichlorophenyl)ethylN-methyl-1-pyrrolidineethanamine is a selective sigma receptor antagonist, with a reported binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biom ...

BD-1047 BD-1047 is a sigma receptor antagonist, selective for the σ1 subtype. It has effects in animal studies suggestive of antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage ...

: selective for σ₁ subtype *

BD1060 BD1060 or ''N''- -(3,4-dichlorophenyl)ethyl1-pyrrolidineethanamine is a selective sigma receptor antagonist, with a reported binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecu ...

: selective for σ₁ subtype * BD1063: selective for σ₁ subtype * BD1067 *

BMY-14802 BMY-14802, also known as BMS-181100, is a drug with antipsychotic effects which acts as both a sigma receptor antagonist and a 5-HT1A receptor agonist. It also has affinity for the 5-HT2 and D4 receptors. The drug reached phase III clinical ...

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 * MT-45 MT-45 (IC-6) is an opioid ...

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

Haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosi ...

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 ov ...

: selective for σ₁ subtype * LR172 * MS-377: selective for σ₁ subtype *

NE-100 NE-100 or 4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine is a selective sigma-1 receptor antagonist, with a reported binding affinity of ''K''i = 1.03 ± 0.01 nM, and more than 205 times selectivity over the sigma-2 receptor. NE- ...

: 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 antagonis ...

Phenothiazines Phenothiazine, abbreviated PTZ, is an organic compound that has the formula S(C6H4)2NH and is related to the thiazine-class of heterocyclic compounds. Derivatives of phenothiazine are highly bioactive and have widespread use and rich history. Th ...

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 majo ...

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 phencyclidine and cocaine, and rimcazole was o ...

* S1RA (E-52862): selective for σ₁ subtype *

Sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the diffe ...

* UMB100 * UMB101 * UMB103 * UMB116 * YZ-011 * YZ-069 * YZ-185

References

External links

* {{Sigma receptor modulators Receptors