sigma non-opioid intracellular receptor 1 | Sigma receptors | IUPHAR Guide to IMMUNOPHARMACOLOGY

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sigma non-opioid intracellular receptor 1

  Target has curated data in GtoImmuPdb

Target id: 2552

Nomenclature: sigma non-opioid intracellular receptor 1

Family: Sigma receptors

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 223 9p13.3 SIGMAR1 sigma non-opioid intracellular receptor 1
Mouse 2 223 4 Sigmar1 sigma non-opioid intracellular receptor 1
Rat 2 223 5q22 Sigmar1 sigma non-opioid intracellular receptor 1
Previous and Unofficial Names
σ1 | opioid receptor, sigma 1 | OPRS1 | SIG-1R | sigma 1-type opioid receptor | Sigma1R
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
(RS)-PPCC Hs Agonist 8.8 pKi 11
pKi 8.8 [11]
1,3-ditolylguanidine Cp Full agonist 7.4 pKi 6
pKi 7.4 (Ki 3.545x10-8 M) [6]
dextromethorphan Hs Agonist 6.3 pKi 4
pKi 6.3 (Ki 5.21x10-7 M) [4]
Description: Sigma receptor cloned from Jurkat cells, identified as SIGMAR1.
PRE-084 Hs Agonist 7.4 pIC50 14
pIC50 7.4 [14]
(+)-SKF 10.047 Hs Agonist - -
[3H]pentazocine Hs Agonist - -
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PD-144418 Mm Antagonist 10.1 pKi 1
pKi 10.1 (Ki 8x10-11 M) [1]
Description: Displacement of [3H](+)-pentazocine from sigma1 sites on membranes from NG 108-15 neuroblastoma X glioma rat/mouse hybrid cells
E-52862 Hs Antagonist 7.8 pKi 3
pKi 7.8 (Ki 1.7x10-8 M) [3]
Description: Binding affinity to human σ1R in transfected HEK-293 membranes using [3H](+)-pentazocine as radioligand.
fluvoxamine Hs Antagonist 7.4 pKi 16
pKi 7.4 (Ki 3.6x10-8 M) [16]
NE-100 Hs Antagonist 8.4 pIC50 10
pIC50 8.4 [10]
BD-1047 Hs Antagonist 7.4 pIC50 8
pIC50 7.4 [8]
(-)-pentazocine Hs Antagonist - -
View species-specific antagonist tables
Antagonist Comments
The σ receptor is the likely primary target of the approved drug pentazocine (racemic mixture), although the interaction is shown in the antagonist table above with (-)-pentazocine.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
vanoxerine Rn Binding 7.3 pIC50 2
pIC50 7.3 (IC50 4.8x10-8 M) [2]
Immunopharmacology Comments
Experimental evidence indicates that the sigma 1 (σ1) receptor is a key regulator of the IRE1-driven inflammatory response that arise from stress detection within the endoplasmic reticulum [7,9,12]. Pharmacologic and genetic σ1 modulation have been shown to influence immune cells and cytokine production in vitro [13,15]. Targeting σ1 is considered as a potential therapeutic mechanism for inflammatory diseases that would avoid disrupting IRE1's important homeostatic functions. Work by Rosen et al. (2019) has demonstrated the protective effects of σ1 modulation in preclinical models of inflammation and sepsis [13].
Clinically-Relevant Mutations and Pathophysiology
Disease:  Amyotrophic lateral sclerosis 16, juvenile; ALS16
Synonyms: Juvenile amyotrophic lateral sclerosis [Orphanet: ORPHA300605]
OMIM: 614373
Orphanet: ORPHA300605
General Comments
SARS-CoV-2/COVID-19
Experimental in vitro evidence, using affinity-purification mass spectrometry (AP-MS), indicates a protein-protein interaction between SIGMAR1 and the SARS-CoV-2 non-structural protein 6 (Nsp6) [5], although whether this interaction is realistic based on spatial distribution of the host and viral proteins within cells was not addressed in this study. Speculatively, SIGMAR1 ligands such as E-52862 or PD-144418 could be utilised to examine the effect of inhibiting the SIGMAR1/Nsp6 protein-protein interaction on SARS-CoV-2 pathobiology.

References

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1. Akunne HC, Whetzel SZ, Wiley JN, Corbin AE, Ninteman FW, Tecle H, Pei Y, Pugsley TA, Heffner TG. (1997) The pharmacology of the novel and selective sigma ligand, PD 144418. Neuropharmacology, 36 (1): 51-62. [PMID:9144641]

2. Contreras PC, Bremer ME, Rao TS. (1990) GBR-12909 and fluspirilene potently inhibited binding of [3H] (+)3-PPP to sigma receptors in rat brain. Life Sci., 47 (22): PL133-7. [PMID:1980329]

3. Díaz JL, Cuberes R, Berrocal J, Contijoch M, Christmann U, Fernández A, Port A, Holenz J, Buschmann H, Laggner C et al.. (2012) Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862). J. Med. Chem., 55 (19): 8211-24. [PMID:22784008]

4. Ganapathy ME, Prasad PD, Huang W, Seth P, Leibach FH, Ganapathy V. (1999) Molecular and ligand-binding characterization of the sigma-receptor in the Jurkat human T lymphocyte cell line. J. Pharmacol. Exp. Ther., 289 (1): 251-60. [PMID:10087012]

5. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL et al.. (2020) A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature, [Epub ahead of print]. [PMID:32353859]

6. Lever JR, Gustafson JL, Xu R, Allmon RL, Lever SZ. (2006) Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503. Synapse, 59 (6): 350-8. [PMID:16463398]

7. Martinon F, Chen X, Lee AH, Glimcher LH. (2010) TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol., 11 (5): 411-8. [PMID:20351694]

8. Matsumoto RR, Bowen WD, Tom MA, Vo VN, Truong DD, De Costa BR. (1995) Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism. Eur. J. Pharmacol., 280 (3): 301-10. [PMID:8566098]

9. Mori T, Hayashi T, Hayashi E, Su TP. (2013) Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLoS ONE, 8 (10): e76941. [PMID:24204710]

10. Okuyama S, Imagawa Y, Ogawa S, Araki H, Ajima A, Tanaka M, Muramatsu M, Nakazato A, Yamaguchi K, Yoshida M et al.. (1993) NE-100, a novel sigma receptor ligand: in vivo tests. Life Sci., 53 (18): PL285-90. [PMID:7901723]

11. Prezzavento O, Campisi A, Ronsisvalle S, Li Volti G, Marrazzo A, Bramanti V, Cannavò G, Vanella L, Cagnotto A, Mennini T et al.. (2007) Novel sigma receptor ligands: synthesis and biological profile. J. Med. Chem., 50 (5): 951-61. [PMID:17328523]

12. Qiu Q, Zheng Z, Chang L, Zhao YS, Tan C, Dandekar A, Zhang Z, Lin Z, Gui M, Li X et al.. (2013) Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J., 32 (18): 2477-90. [PMID:23942232]

13. Rosen DA, Seki SM, Fernández-Castañeda A, Beiter RM, Eccles JD, Woodfolk JA, Gaultier A. (2019) Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med, 11 (478). [PMID:30728287]

14. Su TP, Wu XZ, Cone EJ, Shukla K, Gund TM, Dodge AL, Parish DW. (1991) Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand. J. Pharmacol. Exp. Ther., 259 (2): 543-50. [PMID:1658302]

15. Szabo A, Kovacs A, Frecska E, Rajnavolgyi E. (2014) Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLoS ONE, 9 (8): e106533. [PMID:25171370]

16. Yu LF, Zhang HK, Gunosewoyo H, Kozikowski AP. (2012) From α4β2 Nicotinic Ligands to the Discovery of σ1 Receptor Ligands: Pharmacophore Analysis and Rational Design. ACS Med Chem Lett, 3 (12): 1054-1058. [PMID:23641311]

How to cite this page

Sigma receptors: sigma non-opioid intracellular receptor 1. Last modified on 27/03/2020. Accessed on 20/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2552.