Sigma-1 receptor

The mammalian σ₁ receptor is an integral membrane protein composed of 223 amino acids.{{cite journal | vauthors = Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H | title = Purification, molecular cloning, and expression of the mammalian sigma1-binding site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 15 | pages = 8072–8077 | date = July 1996 | pmid = 8755605 | pmc = 38877 | doi = 10.1073/pnas.93.15.8072 | doi-access = free | bibcode = 1996PNAS...93.8072H }} Despite being found in mammals, it shows no sequence homology to other mammalian proteins. However, it shares 30% sequence identity and 69% similarity with the ERG2 gene product of yeast, a C8–C7 sterol isomerase involved in the ergosterol biosynthesis pathway. Hydropathy analysis reveals three hydrophobic regions within the σ₁ receptor.{{cite journal | vauthors = Moebius FF, Striessnig J, Glossmann H | title = The mysteries of sigma receptors: new family members reveal a role in cholesterol synthesis | journal = Trends in Pharmacological Sciences | volume = 18 | issue = 3 | pages = 67–70 | date = March 1997 | pmid = 9133773 | doi = 10.1016/s0165-6147(96)01037-1 }} A crystal structure of the human σ₁ receptor was first published in 2016.{{cite journal | vauthors = Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC | title = Crystal structure of the human σ₁ receptor | journal = Nature | volume = 532 | issue = 7600 | pages = 527–530 | date = April 2016 | pmid = 27042935 | pmc = 5550834 | doi = 10.1038/nature17391 | bibcode = 2016Natur.532..527S }}

The sigma-1 receptor is a small, unique integral membrane protein predominantly localized to the endoplasmic reticulum (ER). It is structurally distinct from all other known mammalian proteins. High-resolution crystal structures have shown that the receptor forms a homotrimer, with each protomer consisting of a single N-terminal transmembrane helix, a cupin-like β-barrel domain that contains the ligand-binding site, and a C-terminal V-shaped two-helix bundle that functions as a lid over this pocket.{{cite journal | vauthors = Meng F, Xiao Y, Ji Y, Sun Z, Zhou X | title = An open-like conformation of the sigma-1 receptor reveals its ligand entry pathway | journal = Nature Communications | volume = 13 | issue = 1 | pages = 1267 | date = March 2022 | pmid = 35273182 | pmc = 8913746 | doi = 10.1038/s41467-022-28946-w | bibcode = 2022NatCo..13.1267M }}{{cite journal | vauthors = Ryskamp DA, Korban S, Zhemkov V, Kraskovskaya N, Bezprozvanny I | title = Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases | journal = Frontiers in Neuroscience | volume = 13 | pages = 862 | date = 2019 | pmid = 31551669 | pmc = 6736580 | doi = 10.3389/fnins.2019.00862 | doi-access = free }} The ligand-binding pocket is highly conserved and predominantly hydrophobic, shielded from the aqueous environment. Key residues such as Glu172 and Asp126 play crucial roles in coordinating ligand interactions. This structural organization enables the receptor to bind a wide variety of ligands and interact with multiple effector proteins. Conformational changes in the β-barrel domain and the helical lid are believed to regulate ligand access and receptor activation. The receptor's architecture supports its function as a chaperone and modulator of numerous intracellular signaling pathways.{{cite book | vauthors = Ossa F, Schnell JR, Ortega-Roldan JL | chapter = A Review of the Human Sigma-1 Receptor Structure | title = Sigma Receptors: Their Role in Disease and as Therapeutic Targets | series = Advances in Experimental Medicine and Biology | volume = 964 | pages = 15–29 | date = 2017 | pmid = 28315262 | doi = 10.1007/978-3-319-50174-1_3 | isbn = 978-3-319-50172-7 }}

A variety of specific physiological functions have been attributed to the σ₁ receptor. Chief among these are modulation of Ca²⁺ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K⁺ channels.{{cite journal | vauthors = Monassier L, Bousquet P | title = Sigma receptors: from discovery to highlights of their implications in the cardiovascular system | journal = Fundamental & Clinical Pharmacology | volume = 16 | issue = 1 | pages = 1–8 | date = February 2002 | pmid = 11903506 | doi = 10.1046/j.1472-8206.2002.00063.x | s2cid = 27932111 }} The reasons for these effects are not well understood, even though σ₁ receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between σ₁ receptors and G-proteins have been suggested such as σ₁ receptor antagonists showing GTP-sensitive high-affinity binding;{{cite journal | vauthors = Brimson JM, Brown CA, Safrany ST | title = Antagonists show GTP-sensitive high-affinity binding to the sigma-1 receptor | journal = British Journal of Pharmacology | volume = 164 | issue = 2b | pages = 772–780 | date = September 2011 | pmid = 21486275 | pmc = 3188898 | doi = 10.1111/j.1476-5381.2011.01417.x }} there is also, however, some evidence against a G-protein coupled hypothesis.{{cite journal | vauthors = Hong W, Werling LL | title = Evidence that the sigma(1) receptor is not directly coupled to G proteins | journal = European Journal of Pharmacology | volume = 408 | issue = 2 | pages = 117–125 | date = November 2000 | pmid = 11080517 | doi = 10.1016/S0014-2999(00)00774-3 }} The σ₁ receptor has been shown to appear in a complex with voltage gated K⁺ channels (K_v1.4 and K_v1.5), leading to the idea that σ₁ receptors are auxiliary subunits.{{cite journal | vauthors = Lupardus PJ, Wilke RA, Aydar E, Palmer CP, Chen Y, Ruoho AE, Jackson MB | title = Membrane-delimited coupling between sigma receptors and K+ channels in rat neurohypophysial terminals requires neither G-protein nor ATP | journal = The Journal of Physiology | volume = 526 | issue = 3 | pages = 527–539 | date = August 2000 | pmid = 10922005 | pmc = 2270035 | doi = 10.1111/j.1469-7793.2000.00527.x }} σ₁ receptors apparently co-localize with IP₃ receptors on the endoplasmic reticulum{{cite journal | vauthors = Hayashi T, Su TP | title = Regulating ankyrin dynamics: Roles of sigma-1 receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 2 | pages = 491–496 | date = January 2001 | pmid = 11149946 | pmc = 14614 | doi = 10.1073/pnas.021413698 | doi-access = free }} where they may be involved in preventing endoplasmic reticulum stress in neurodegenerative diseases.{{cite journal | vauthors = Brimson JM, Safrany ST, Qassam H, Tencomnao T | title = Dipentylammonium Binds to the Sigma-1 Receptor and Protects Against Glutamate Toxicity, Attenuates Dopamine Toxicity and Potentiates Neurite Outgrowth in Various Cultured Cell Lines | journal = Neurotoxicity Research | volume = 34 | issue = 2 | pages = 263–272 | date = August 2018 | pmid = 29589276 | doi = 10.1007/s12640-018-9883-5 | s2cid = 4378593 }} Also, σ₁ receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.{{cite journal | vauthors = Hayashi T, Su TP | title = Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 41 | pages = 14949–14954 | date = October 2004 | pmid = 15466698 | pmc = 522002 | doi = 10.1073/pnas.0402890101 | doi-access = free | bibcode = 2004PNAS..10114949H }} The wide scope and effect of ligand binding on σ₁ receptors has led some to believe that σ₁ receptors are intracellular signal transduction amplifiers.

Recently, σ₁R has been implicated in autophagosome formation {{cite journal | vauthors = Kumar S, Javed R, Mudd M, Pallikkuth S, Lidke KA, Jain A, Tangavelou K, Gudmundsson SR, Ye C, Rusten TE, Anonsen JH, Lystad AH, Claude-Taupin A, Simonsen A, Salemi M, Phinney B, Li J, Guo LW, Bradfute SB, Timmins GS, Eskelinen EL, Deretic V | title = Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes | journal = Cell | volume = 184 | issue = 24 | pages = 5950–5969.e22 | date = November 2021 | pmid = 34741801 | pmc = 8616855 | doi = 10.1016/j.cell.2021.10.017 }} and maturation.{{cite journal | vauthors = Yang H, Shen H, Li J, Guo LW | title = SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance | journal = Autophagy | volume = 15 | issue = 9 | pages = 1539–1557 | date = September 2019 | pmid = 30871407 | pmc = 6693456 | doi = 10.1080/15548627.2019.1586248 }} Autophagy is a broad homeostatic, metabolic, cytoplasmic quality control, and metabolic process affecting many functions in the cell.{{cite journal | vauthors = Levine B, Kroemer G | title = Biological Functions of Autophagy Genes: A Disease Perspective | journal = Cell | volume = 176 | issue = 1–2 | pages = 11–42 | date = January 2019 | pmid = 30633901 | pmc = 6347410 | doi = 10.1016/j.cell.2018.09.048 }} σ₁R is targeted by the nsp6 protein of SARS-CoV-2{{cite journal | vauthors = Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZ, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJ, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JC, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ | title = A SARS-CoV-2 protein interaction map reveals targets for drug repurposing | journal = Nature | volume = 583 | issue = 7816 | pages = 459–468 | date = July 2020 | pmid = 32353859 | pmc = 7431030 | doi = 10.1038/s41586-020-2286-9 | bibcode = 2020Natur.583..459G }} to inhibit autophagosome formation as a process competing with the coronavirus for cellular endomembranes that the virus needs for its own replication. This along with the observed beneficial effects of sigma-1 receptor agonist and SSRI fluvoxamine in patients with SARS-COV-2 infection{{cite journal | vauthors = Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, Miller JP, Yang L, Yingling M, Avidan MS, Reiersen AM | title = Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial | journal = JAMA | volume = 324 | issue = 22 | pages = 2292–2300 | date = December 2020 | pmid = 33180097 | doi = 10.1001/jama.2020.22760 | pmc = 7662481 }} has led to the hypothesis that the sigma-1 receptor could be a target for the treatment of SARS-COV-2.{{cite journal | vauthors = Brimson JM, Prasanth MI, Malar DS, Brimson S, Thitilertdecha P, Tencomnao T | title = Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy | journal = Expert Opinion on Therapeutic Targets | volume = 25 | issue = 6 | pages = 435–449 | date = June 2021 | pmid = 34236922 | doi = 10.1080/14728222.2021.1952987 | pmc = 8290373 }}

The σ₁ receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of N-allylnormetazocine (SKF-10,047) could not be due to activity at the μ and κ receptors (named from the first letter of their selective ligands morphine and ketazocine, respectively) and a new type of opioid receptor was proposed; σ (from the first letter of SKF-10,047).{{cite journal | vauthors = Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE | title = The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 197 | issue = 3 | pages = 517–532 | date = June 1976 | pmid = 945347 }} The opioid classification was eventually dropped however resulting from it not possessing the canonical opioid G-protein coupled receptor structure and the receptor was later referred to as simply the σ₁ receptor. It was found to have affinity for the (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), as well as various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol (which irreversibly blocks this receptor{{cite journal | vauthors = Cobos EJ, del Pozo E, Baeyens JM | title = Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells | journal = Journal of Neurochemistry | volume = 102 | issue = 3 | pages = 812–825 | date = August 2007 | pmid = 17419803 | doi = 10.1111/j.1471-4159.2007.04533.x }}) and cocaine, and neuroactive steroids like progesterone.{{cite journal | vauthors = Su TP, Hayashi T | title = Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction | journal = Current Medicinal Chemistry | volume = 10 | issue = 20 | pages = 2073–2080 | date = October 2003 | pmid = 12871086 | doi = 10.2174/0929867033456783 | url = https://zenodo.org/record/1235850 }}

Pharmacological studies with σ₁ agonists often follow a bell-shaped dose-response curve. Thus care should be taken when designing experiments and choosing doses of ligands.

The following ligands have high affinity for the σ₁ receptor and possess high binding selectivity over the subtype σ₂:{{cite journal | vauthors = Sambo DO, Lebowitz JJ, Khoshbouei H | title = The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction | journal = Pharmacology & Therapeutics | volume = 186 | pages = 152–167 | date = June 2018 | pmid = 29360540 | pmc = 5962385 | doi = 10.1016/j.pharmthera.2018.01.009 }}

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• Amantadine
• Amitriptyline
• Blarcamesine
• Citalopram
• Cocaine
• Cutamesine
• Dextromethorphan
• Dimethoxanate
• Dimethyltryptamine
• Dipentylamine and its hydrochloride salt (dipentylammonium chloride){{cite journal | vauthors = Brimson JM, Akula KK, Abbas H, Ferry DR, Kulkarni SK, Russell ST, Tisdale MJ, Tencomnao T, Safrany ST | title = Simple ammonium salts acting on sigma-1 receptors yield potential treatments for cancer and depression | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 9251 | date = June 2020 | pmid = 32514120 | doi = 10.1038/s41598-020-65849-6 | pmc = 7280195 | bibcode = 2020NatSR..10.9251B }}
• Donepezil
• Fabomotizole{{cite journal | vauthors = Katnik C, Garcia A, Behensky AA, Yasny IE, Shuster AM, Seredenin SB, Petrov AV, Seifu S, McAleer J, Willing A, Cuevas J | title = Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes | journal = Neurobiol Dis | volume = 62 | pages = 354–364 | date = February 2014 | pmid = 24141021| doi = 10.1016/j.nbd.2013.10.011 }}
• Fluoxetine
• Fluvoxamine
• L-687,384
• Methamphetamine
• Opipramol
• (+)-Pentazocine (the "unnatural" enantiomer, which lacks affinity for the μ-opioid and κ-opioid receptors.)
• Pipazetate
• Pitolisant
• PRE-084

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• BD 1047
• FTC-146
• Sertraline
• S1RA (E-52862)
• NE-100
• WQ-1
• 1-benzyl-6′-methoxy-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3.2-c]pyran]: putative antagonist, selective against 5-HT_1A, 5-HT₆, 5-HT₇, α_1A and α₂ adrenergic, and NMDA receptors{{cite journal | vauthors = Oberdorf C, Schepmann D, Vela JM, Diaz JL, Holenz J, Wünsch B | title = Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans] | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 20 | pages = 6531–6537 | date = October 2008 | pmid = 18816044 | doi = 10.1021/jm8007739 }}

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• Methylphenylpiracetam{{cite journal | year = 2015 | title = Novel positive allosteric modulators of sigma-1 receptor | vauthors = Vavers E, Zvejniece L, Veinberg G, Svalbe B, Domracheva I, Vilskersts R, Dambrova M | doi = 10.1186/2193-1801-4-S1-P51 | quote = The R-configuration enantiomers of methylphenylpiracetam are more active positive allosteric modulators of Sigma-1 receptor than S-configuration enantiomers. | volume=4 | journal=SpringerPlus | issue = Suppl 1 | pages=51| pmc = 4797911 | doi-access = free }}{{Better source needed|reason=primary-source poster presentation, does not appear to be peer-reviewed|date=April 2016}}
• SOMCL-668{{cite journal | vauthors = Wang Y, Guo L, Jiang HF, Zheng LT, Zhang A, Zhen XC | title = Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity | journal = CNS Neuroscience & Therapeutics | volume = 22 | issue = 5 | pages = 368–377 | date = May 2016 | pmid = 26854125 | pmc = 6492821 | doi = 10.1111/cns.12502 }}

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• Clorgiline
• D-Deprenyl
• PD 144418
• RHL-033
• Selegiline
• 4-IPBS
• Spipethiane
• (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine{{cite journal | vauthors = Berardi F, Loiodice F, Fracchiolla G, Colabufo NA, Perrone R, Tortorella V | title = Synthesis of chiral 1-[Ω-(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at σ₁, σ₂, and sterol Δ8–Δ7 isomerase sites | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 11 | pages = 2117–2124 | date = May 2003 | pmid = 12747784 | doi = 10.1021/jm021014d }}
• 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]{{cite journal | vauthors = Grosse Maestrup E, Wiese C, Schepmann D, Hiller A, Fischer S, Scheunemann M, Brust P, Wünsch B | title = Synthesis of spirocyclic sigma1 receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability | journal = Bioorganic & Medicinal Chemistry | volume = 17 | issue = 10 | pages = 3630–3641 | date = May 2009 | pmid = 19394833 | doi = 10.1016/j.bmc.2009.03.060 }}
• 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine]{{cite journal | vauthors = Schläger T, Schepmann D, Würthwein EU, Wünsch B | title = Synthesis and structure-affinity relationships of novel spirocyclic sigma receptor ligands with furopyrazole structure | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 6 | pages = 2992–3001 | date = March 2008 | pmid = 18221879 | doi = 10.1016/j.bmc.2007.12.045 }}
• 3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity{{cite journal | vauthors = Zampieri D, Grazia Mamolo M, Laurini E, Zanette C, Florio C, Collina S, Rossi D, Azzolina O, Vio L | title = Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the sigma1 binding site | journal = European Journal of Medicinal Chemistry | volume = 44 | issue = 1 | pages = 124–130 | date = January 2009 | pmid = 18440098 | doi = 10.1016/j.ejmech.2008.03.011 }}

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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.{{cite patent | country = EP | number = 1787679 | title = Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain | inventor = Buschman HH | assign1 = Esteve Pharmaceuticals SA | pubdate = 23 May 2007}}{{cite journal | vauthors = Lee IT, Chen S, Schetz JA | title = An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones | journal = European Journal of Pharmacology | volume = 578 | issue = 2–3 | pages = 123–136 | date = January 2008 | pmid = 17961544 | pmc = 2963108 | doi = 10.1016/j.ejphar.2007.09.020 }}

Mutations in the SIGMAR1 gene have been associated with distal spinal muscular atrophy type 2.{{cite journal | vauthors = Li X, Hu Z, Liu L, Xie Y, Zhan Y, Zi X, Wang J, Wu L, Xia K, Tang B, Zhang R | title = A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy | journal = Neurology | volume = 84 | issue = 24 | pages = 2430–2437 | date = June 2015 | pmid = 26078401 | doi = 10.1212/WNL.0000000000001680 | s2cid = 22155027 }}

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.{{cite journal | vauthors = Brimson JM, Brimson S, Chomchoei C, Tencomnao T | title = Using sigma-ligands as part of a multi-receptor approach to target diseases of the brain | journal = Expert Opinion on Therapeutic Targets | volume = 24 | issue = 10 | pages = 1009–1028 | date = October 2020 | pmid = 32746649 | doi = 10.1080/14728222.2020.1805435 | s2cid = 225218231 }} The activation of autophagy has also been suggested as a downstream mechanism linked to sigma-1 receptor activation.{{cite journal | vauthors = Prasanth MI, Malar DS, Tencomnao T, Brimson JM | title = The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer's | journal = Expert Opinion on Therapeutic Targets | volume = 25 | issue = 5 | pages = 401–414 | date = May 2021 | pmid = 34110944 | doi = 10.1080/14728222.2021.1939681 | s2cid = 235402107 }}

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(Sig-1R) has emerged as a promising therapeutic strategy across multiple neurological, psychiatric, and degenerative conditions. The receptor’s role as a molecular chaperone at the endoplasmic reticulum (ER)-mitochondria interface and its modulation of calcium signaling, neurotransmitter systems, and cellular stress responses underpin its therapeutic potential.

Sig-1R ligands show efficacy in preclinical models of depression, anxiety, and schizophrenia. Antidepressants like fluvoxamine and sertraline act partly through Sig-1R agonism, enhancing synaptic plasticity and restoring excitatory/inhibitory balance.{{cite journal | vauthors = Cobos EJ, Entrena JM, Nieto FR, Cendán CM, Del Pozo E | title = Pharmacology and therapeutic potential of sigma(1) receptor ligands | journal = Current Neuropharmacology | volume = 6 | issue = 4 | pages = 344–366 | date = December 2008 | pmid = 19587856 | pmc = 2701284 | doi = 10.2174/157015908787386113 }} Clinical trials with selective agonists (e.g., SA4503, pridopidine) have demonstrated mixed results, but the receptor remains a focus for developing fast-acting antidepressants.{{cite journal | vauthors = Ren P, Wang J, Li N, Li G, Ma H, Zhao Y, Li Y | title = Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development | journal = Frontiers in Pharmacology | volume = 13 | pages = 925879 | date = 2022 | pmid = 35784746 | pmc = 9243434 | doi = 10.3389/fphar.2022.925879 | doi-access = free }}{{cite journal | vauthors = Ye N, Qin W, Tian S, Xu Q, Wold EA, Zhou J, Zhen XC | title = Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases | journal = Journal of Medicinal Chemistry | volume = 63 | issue = 24 | pages = 15187–15217 | date = December 2020 | pmid = 33111525 | doi = 10.1021/acs.jmedchem.0c01192 }}

In amyotrophic lateral sclerosis (ALS), Sig-1R agonists (PRE-084, SA4503) improve motor function and motoneuron survival in animal models by modulating ER stress and autophagy.{{cite journal | vauthors = Gaja-Capdevila N, Hernández N, Navarro X, Herrando-Grabulosa M | title = Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1G93A ALS Mice | journal = Frontiers in Pharmacology | volume = 12 | pages = 780588 | date = 2021 | pmid = 34955848 | pmc = 8702863 | doi = 10.3389/fphar.2021.780588 | doi-access = free }}{{cite journal | vauthors = Herrando-Grabulosa M, Gaja-Capdevila N, Vela JM, Navarro X | title = Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis | journal = British Journal of Pharmacology | volume = 178 | issue = 6 | pages = 1336–1352 | date = March 2021 | pmid = 32761823 | doi = 10.1111/bph.15224 }} Similarly, Sig-1R activation shows neuroprotective effects in Alzheimer’s and Parkinson’s models, potentially slowing disease progression.

Despite setbacks in clinical trials (e.g., igmesine for depression), the receptor’s broad regulatory roles continue to drive drug discovery, with candidates like ANAVEX2-73 and T-817MA in development for cognitive disorders.{{cite journal | vauthors = Knowles LG, Armanious AJ, Peng Y, Welsh WJ, James MH | title = Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking | journal = Addiction Neuroscience | volume = 8 | date = December 2023 | pmid = 37753198 | pmc = 10519676 | doi = 10.1016/j.addicn.2023.100126 }}

σ₁ receptor knockout mice were created in 2003 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype.{{cite journal | vauthors = Langa F, Codony X, Tovar V, Lavado A, Giménez E, Cozar P, Cantero M, Dordal A, Hernández E, Pérez R, Monroy X, Zamanillo D, Guitart X, Montoliu L | title = Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice | journal = The European Journal of Neuroscience | volume = 18 | issue = 8 | pages = 2188–2196 | date = October 2003 | pmid = 14622179 | doi = 10.1046/j.1460-9568.2003.02950.x | s2cid = 85814812 }} 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.

• Sigma-2 receptor

{{Reflist|33em}}

• {{MeshName|sigma-1+receptor}}
• {{UCSC genome browser|SIGMAR1}}
• {{UCSC gene details|SIGMAR1}}

{{Neuropeptide receptors}}

{{Sigma receptor modulators}}