Sigma receptors (σ-receptors) are
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
s that bind
ligand
In coordination chemistry, a ligand is an ion or molecule with a 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 el ...
s such as
4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine),
SA 4503 (cutamesine),
ditolylguanidine,
dimethyltryptamine
Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a Psychedelic drug, serotonergic hallucinogen and Investigational New Drug, investigational drug of the substituted tryptamine, tryptamine family tha ...
, and
siramesine. There are two subtypes,
sigma-1 receptor
The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a Chaperone (protein), chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by ...
s (σ
1) and
sigma-2 receptors (σ
2), 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 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 σ
1 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 is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
,
morphine
Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
/
diacetylmorphine,
opipramol,
PCP,
fluvoxamine,
methamphetamine
Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...
,
dextromethorphan
Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
, and
berberine
Berberine is a Quaternary ammonium cation, quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids, occurring naturally as a secondary metabolite in some plants including species of ''Berberis'', from which its name ...
. 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
Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
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 ma ...
.
Another endogenous ligand,
''N'',''N''-dimethyltryptamine, was also found to interact with σ
1.
Physiologic effects
Physiologic effects when the σ-receptor is activated include
hypertonia,
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 effects, and
mydriasis
Mydriasis is the Pupillary dilation, dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, Physical trauma, trauma, or the use of c ...
. 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
Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.
Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
-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 σ
1 subtype, Ki = 42nM
*
4-PPBP
*
Afobazole: selective for σ
1 subtype
*
Allylnormetazocine (SKF-10047)
*
Anavex 2-73
*
Arketamine
*
BD1031: selective for σ
1 subtype
*
BD1052: selective for σ
1 subtype
*
Berberine
Berberine is a Quaternary ammonium cation, quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids, occurring naturally as a secondary metabolite in some plants including species of ''Berberis'', from which its name ...
*
Citalopram
*
Cocaine
Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
*
Dehydroepiandrosterone (DHEA)
*
Dehydroepiandrosterone sulfate (DHEA-S)
*
Dextromethorphan
Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
(DXM): relatively selective for σ
1 subtype
*
Dextrorphan
*
''N'',''N''-Dimethyltryptamine (DMT)
*
Dimemorfan
*
Ditolylguanidine
*
Escitalopram
Escitalopram ( ), sold under the brand names Lexapro and Cipralex, among others, is an antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class. It is mainly used to treat major depressive disorder, generalized ...
*
Fluoxetine
*
Fluvoxamine
*
Igmesine
*
Ketamine
Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...
*
L-687,384: selective for σ
1 subtype (&
Spipethiane).
*
Lamotrigine
*
Memantine:
selective for σ
1 subtype, low affinity
*
Methamphetamine
Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...
*
Methylphenidate
Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
*
Noscapine
*
OPC-14523
*
Opipramol
*
PB-28: selective for σ
2 subtype
*
Pentazocine
*
Pentoxyverine: selective for σ
1 subtype
*
Phencyclidine
*
(+)-3-PPP
*
PRE-084: selective for σ
1 subtype
*
Pregnenolone
*
Pregnenolone sulfate
*
SA 4503: selective for σ
1 subtype
*
Siramesine
*
UMB23
*
UMB82
Antagonists
*
AC927
*
AHD1
AZ-66*
BD1008
*
BD-1047: selective for σ
1 subtype
*
BD1060: selective for σ
1 subtype
*
BD1063: selective for σ
1 subtype
*
BD1067
*
BMY-14802
*
CM156: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo
hiazole-2(3H)-thione
*
Haloperidol
*
LR132: selective for σ
1 subtype
LR172*
MS-377: selective for σ
1 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-100 ...
: selective for σ
1 subtype
*
Panamesine
*
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 ma ...
*
Rimcazole
*
S1RA (E-52862): selective for σ
1 subtype
*
Sertraline
*
UMB 98 &
UMB 99
UMB100*
UMB101
*
UMB103
*
UMB116
YZ-011YZ-067
YZ-069
YZ-185
ref>
References
External links
*
{{Sigma receptor modulators
Receptors