Sigma-1 receptor
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The sigma-1 receptor (σ1R), one of two
The σ1 receptor is a
Much is known about the binding affinity of hundreds of synthetic compounds to the σ1 receptor.An endogenous
Characteristics
The σ1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of
Structure
The mammalian σ1 receptor is an integral membrane protein with 223 amino acids.[16] It shows no homology to other mammalian proteins but strikingly shares 30% sequence identity and 69% similarity with the ERG2 gene product of yeast, which is a C8-C7 sterol isomerase in the ergosterol biosynthetic pathway. Hydropathy analysis of the σ1 receptor indicates three hydrophobic regions.[17] A crystal structure of the σ1 receptor was published in 2016.[18]
Functions
A variety of specific physiological functions have been attributed to the σ1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac
Recently, σ1R has been implicated in
There has been much interest in the sigma-1 receptor and its role in age-related neurodegenerative diseases such as Alzheimer's disease. During healthy ageing, the density of sigma-1 receptors has been to increase. However, in diseases such as Alzheimer's disease, there appears to be a reduction in sigma-1 receptor expression. It has been suggested that targeting the sigma-1 receptor along with other receptors could increase neuron survival and function in neurodegenerative disease.[15] The activation of autophagy has also been suggested as a downstream mechanism linked to sigma-1 receptor activation.[32]
Knockout mice
σ1 receptor knockout mice were created in 2003 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype.[33] As expected, however, they did lack locomotor response to the σ ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the σ family (e.g., σ2, with similar binding properties) to compensate for the lack of σ1 receptor.[33]
Clinical significance
Mutations in the SIGMAR1 gene have been associated with distal spinal muscular atrophy type 2.[34]
Ligands
The following ligands have high affinity for the σ1 receptor and possess high binding selectivity over the subtype σ2:
Agonists:
- PRE-084
- Blarcamesine
- Donepezil
- Fluvoxamine
- Fluoxetine
- Citalopram
- Amitriptyline
- Cocaine
- L-687,384
- Cutamesine
- Dipentylamine and its hydrochloride salt (dipentylammonium chloride)[35][36]
- Dextromethorphan
- Dimethyltryptamine
- (+)-κ-opioidreceptors.)
- Opipramol
Antagonists:
- Methamphetamine
- Selegiline
- D-Deprenyl
- Sertraline
- S1RA
- FTC-146
- 1-benzyl-6′-methoxy-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3.2-c]pyran]: putative antagonist, selective against 5-HT1A, 5-HT6, 5-HT7, α1A and α2 adrenergic, and NMDA receptors[37]
- NE-100
Positive allosteric modulators (PAMs):
- better source needed]
- SOMCL-668[39]
Uncategorized:
- 4-IPBS
- PD 144418
- Spipethiane
- RHL-033
- 3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity[40]
- 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine][41]
- 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine][42]
- (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine[43]
Agents exist that have high σ1 affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or less dirty/multifunctional, like haloperidol. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.[44][45]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000147955 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036078 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 18885068.
- PMID 8954936.
- S2CID 22305479.
- PMID 2845055.
- S2CID 23606712.
- S2CID 9704436.
- PMID 19213917.
- S2CID 72726251.
- PMID 945347.
- ^ PMID 12871086.
- ^ S2CID 225218231.
- PMID 8755605.
- PMID 9133773.
- PMID 27042935.
- S2CID 27932111.
- PMID 21486275.
- PMID 11080517.
- PMID 10922005.
- PMID 11149946.
- S2CID 4378593.
- PMID 15466698.
- ^ PMID 34741801.
- PMID 30871407.
- PMID 30633901.
- PMID 32353859.
- PMID 33180097.
- PMID 34236922.
- S2CID 235402107.
- ^ S2CID 85814812.
- S2CID 22155027.
- S2CID 4378593.
- PMID 32514120.
- PMID 18816044.
- PMC 4797911.
The R-configuration enantiomers of methylphenylpiracetam are more active positive allosteric modulators of Sigma-1 receptor than S-configuration enantiomers.
- PMID 26854125.
- PMID 18440098.
- PMID 19394833.
- PMID 18221879.
- PMID 12747784.
- ^ EP 1787679, Buschman HH, "Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain", published 23 May 2007, assigned to Esteve Pharmaceuticals SA
- PMID 17961544.
External links
- sigma-1+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- SIGMAR1 human gene location in the UCSC Genome Browser.
- SIGMAR1 human gene details in the UCSC Genome Browser.