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sigma non-opioid intracellular receptor 1

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2552

Nomenclature: sigma non-opioid intracellular receptor 1

Family: Sigma receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 223 9p13.3 SIGMAR1 sigma non-opioid intracellular receptor 1
Mouse 1 223 4 A5 Sigmar1 sigma non-opioid intracellular receptor 1
Rat 1 223 5q22 Sigmar1 sigma non-opioid intracellular receptor 1
Previous and Unofficial Names Click here for help
σ1 | opioid receptor, sigma 1 | OPRS1 | SIG-1R | sigma 1-type opioid receptor | Sigma1R
Database Links Click here for help
Alphafold Q99720 (Hs), O55242 (Mm), Q9R0C9 (Rn)
ChEMBL Target CHEMBL287 (Hs), CHEMBL3465 (Mm), CHEMBL3602 (Rn)
DrugBank Target Q99720 (Hs)
Ensembl Gene ENSG00000147955 (Hs), ENSMUSG00000036078 (Mm), ENSRNOG00000014604 (Rn)
Entrez Gene 10280 (Hs), 18391 (Mm), 29336 (Rn)
Human Protein Atlas ENSG00000147955 (Hs)
KEGG Gene hsa:10280 (Hs), mmu:18391 (Mm), rno:29336 (Rn)
OMIM 601978 (Hs)
Orphanet ORPHA291509 (Hs)
Pharos Q99720 (Hs)
RefSeq Nucleotide NM_147157 (Hs), NM_005866 (Hs), NM_011014 (Mm), NM_030996 (Rn)
RefSeq Protein NP_005857 (Hs), NP_671513 (Hs), NP_035144 (Mm), NP_112258 (Rn)
UniProtKB Q99720 (Hs), O55242 (Mm), Q9R0C9 (Rn)
Wikipedia SIGMAR1 (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
opipramol Small molecule or natural product Approved drug Cp Agonist 9.7 pKi 8
⤷ pKi 9.7 (Ki 2x10-10 M) [8]
(RS)-PPCC Small molecule or natural product Hs Agonist 8.8 pKi 14
⤷ pKi 8.8 [14]
1,3-ditolylguanidine Small molecule or natural product Click here for species-specific activity table Cp Full agonist 7.4 pKi 9
⤷ pKi 7.4 (Ki 3.545x10-8 M) [9]
dextromethorphan Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 6.3 pKi 5
⤷ pKi 6.3 (Ki 5.21x10-7 M) [5]
Description: Sigma receptor cloned from Jurkat cells, identified as SIGMAR1.
PRE-084 Small molecule or natural product Ligand has a PDB structure Hs Agonist 7.4 pIC50 18
⤷ pIC50 7.4 [18]
blarcamesine Small molecule or natural product Hs Agonist 6.1 pIC50 20
⤷ pIC50 6.1 (IC50 8.6x10-7 M) [20]
(+)-SKF 10.047 Small molecule or natural product Hs Agonist - -
⤷
[3H]pentazocine Small molecule or natural product Ligand is labelled Ligand is radioactive 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 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure 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
BD-1063 Small molecule or natural product Hs Antagonist 8.2 pKi 3
⤷ pKi 8.2 (Ki 6.3x10-9 M) [3]
Description: Displacement of [3H](+)pentazocine from human sigma 1 receptor expressed in HEK293 cells, in a membrane radiologand binding assay
E-52862 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand 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.
EST64454 Small molecule or natural product Hs Antagonist 7.7 pKi 4
⤷ pKi 7.7 (Ki 2.2x10-8 M) [4]
Description: Measuring displacement of radiotracer [3H](+)-pentazocine binding to membranes from HEK293 cells expressing human sigma1 receptor.
EST73502 Small molecule or natural product Hs Antagonist 6.9 pKi 6
⤷ pKi 6.9 (Ki 1.18x10-7 M) [6]
NE-100 Small molecule or natural product Ligand has a PDB structure Hs Antagonist 8.4 pIC50 13
⤷ pIC50 8.4 [13]
BD-1047 Small molecule or natural product Hs Antagonist 7.4 pIC50 11
⤷ pIC50 7.4 [11]
(-)-pentazocine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table 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
fluvoxamine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Binding 7.4 pKi 17,21
⤷ pKi 7.4 (Ki 3.6x10-8 M) [17,21]
Description: Binding affinity.
vanoxerine Small molecule or natural product Click here for species-specific activity table 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 [10,12,15]. Pharmacologic and genetic σ1 modulation have been shown to influence immune cells and cytokine production in vitro [16,19]. 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 [16].
Clinically-Relevant Mutations and Pathophysiology Click here for help
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) [7], 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. Díaz JL, García M, Torrens A, Caamaño AM, Enjo J, Sicre C, Lorente A, Port A, Montero A,Yeste S et al.. (2020) EST64454: a Highly Soluble σ 1 Receptor Antagonist Clinical Candidate for Pain Management. J Med Chem, [Online ahead of print]. DOI: 10.1021/acs.jmedchem.0c01575 [PMID:33237785]

5. 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]

6. García M, Virgili M, Alonso M, Alegret C, Farran J, Fernández B, Bordas M, Pascual R, Burgueño J, Vidal-Torres A et al.. (2020) Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ1 Receptor Antagonist Clinical Candidate for the Treatment of Pain. J Med Chem, 63 (24): 15508-15526. [PMID:33064947]

7. 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, 583 (7816): 459-468. [PMID:32353859]

8. Laggner C, Schieferer C, Fiechtner B, Poles G, Hoffmann RD, Glossmann H, Langer T, Moebius FF. (2005) Discovery of high-affinity ligands of sigma1 receptor, ERG2, and emopamil binding protein by pharmacophore modeling and virtual screening. J Med Chem, 48 (15): 4754-64. [PMID:16033255]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. Stahl SM. (2008) The sigma enigma: can sigma receptors provide a novel target for disorders of mood and cognition?. J Clin Psychiatry, 69 (11): 1673-4. [PMID:19200426]

18. 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]

19. 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]

20. Villard V, Espallergues J, Keller E, Vamvakides A, Maurice T. (2011) Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. J Psychopharmacol, 25 (8): 1101-17. [PMID:20829307]

21. 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 26/06/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2552.