Sigma receptor

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.{{cite book | vauthors = Kim FJ, Pasternak GW | chapter = Introduction to Sigma Proteins: Evolution of the Concept of Sigma Receptors | volume = 244 | pages = 1–11 | date = 2017 | pmid = 28871306 | doi = 10.1007/164_2017_41 | publisher = Springer International Publishing | isbn = 978-3-319-65853-7 | series = Handbook of Experimental Pharmacology | title = Sigma Proteins: Evolution of the Concept of Sigma Receptors | place = Cham }} When the σ₁ 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.{{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 = 8072–7 | date = July 1996 | pmid = 8755605 | pmc = 38877 | doi = 10.1073/pnas.93.15.8072 | bibcode = 1996PNAS...93.8072H | doi-access = free }} At this point, they were designated as a separate class of proteins.

The function of these receptors is poorly understood.{{cite journal | vauthors = Leonard BE | title = Sigma receptors and sigma ligands: background to a pharmacological enigma | journal = Pharmacopsychiatry | volume = 37 | pages = S166–70 | date = November 2004 | issue = Suppl 3 | pmid = 15547782 | doi = 10.1055/s-2004-832674 | s2cid = 38914893 }} Drugs known to be σ-agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and berberine.{{Citation needed|date=June 2021}} 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 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. Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ₁.{{cite journal | vauthors = Guitart X, Codony X, Monroy X | title = Sigma receptors: biology and therapeutic potential | journal = Psychopharmacology | volume = 174 | issue = 3 | pages = 301–19 | date = July 2004 | pmid = 15197533 | doi = 10.1007/s00213-004-1920-9 | s2cid = 23606712 }}{{cite journal | vauthors = Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE | title = The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator | journal = Science | volume = 323 | issue = 5916 | pages = 934–7 | date = February 2009 | pmid = 19213917 | pmc = 2947205 | doi = 10.1126/science.1166127 | url = | bibcode = 2009Sci...323..934F }}

Physiologic effects when the σ-receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, and mydriasis.{{Citation needed|date=March 2021}} 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-like effects in mice.{{cite journal | vauthors = Wang J, Mack AL, Coop A, Matsumoto RR | title = Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice | journal = European Neuropsychopharmacology | volume = 17 | issue = 11 | pages = 708–16 | date = November 2007 | pmid = 17376658 | pmc = 4041597 | doi = 10.1016/j.euroneuro.2007.02.007 }}

σ-receptors were also shown to have a role in the regulation of iron/heme homeostasis.{{Cite journal |last1=Nguyen |first1=Nhi T. |last2=Jaramillo-Martinez |first2=Valeria |last3=Mathew |first3=Marilyn |last4=Suresh |first4=Varshini V. |last5=Sivaprakasam |first5=Sathish |last6=Bhutia |first6=Yangzom D. |last7=Ganapathy |first7=Vadivel |date=January 2023 |title=Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis |journal=International Journal of Molecular Sciences |language=en |volume=24 |issue=19 |pages=14672 |doi=10.3390/ijms241914672 |pmid=37834119 |pmc=10572259 |issn=1422-0067 |doi-access=free }}

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• Choline{{ cite web | url = https://www.sciencedaily.com/releases/2019/01/190114113529.htm | title = Researchers identify long-sought activator of sigma receptors in human cells

| access-date = 2022-03-14 | date = 2019-01-14}}

• 3-MeO-PCP:{{ cite web | url = http://www.homeoffice.gov.uk/publications/agencies-public-bodies/acmd1/methoxetamine2012 | title = (ACMD) Methoxetamine Report (2012) | access-date = 2012-10-22 | date = 2012-10-18 | format = PDF | pages = 14 | work = UK Home Office}} selective for σ₁ subtype, Ki = 42nM
• 4-PPBP
• Afobazole: selective for σ₁ subtype
• Allylnormetazocine (SKF-10047)
• Anavex 2-73{{cite journal | vauthors = Maurice T, Su TP | title = The pharmacology of sigma-1 receptors | journal = Pharmacology & Therapeutics | volume = 124 | issue = 2 | pages = 195–206 | date = November 2009 | pmid = 19619582 | pmc = 2785038 | doi = 10.1016/j.pharmthera.2009.07.001 }}
• Arketamine
• BD1031: selective for σ₁ subtype
• BD1052: selective for σ₁ subtype
• Berberine
• Citalopram
• Cocaine
• Dehydroepiandrosterone (DHEA)
• Dehydroepiandrosterone sulfate (DHEA-S)
• Dextromethorphan (DXM): relatively selective for σ₁ subtype
• Dextrorphan
• N,N-Dimethyltryptamine (DMT)
• Dimemorfan
• Ditolylguanidine
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Igmesine
• Ketamine{{cite journal | vauthors = Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J | title = Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET) | journal = European Neuropsychopharmacology | volume = 7 | issue = 1 | pages = 25–38 | date = February 1997 | pmid = 9088882 | doi = 10.1016/S0924-977X(96)00042-9 | s2cid = 26861697 }}{{cite journal | vauthors = Klepstad P, Maurset A, Moberg ER, Oye I | title = Evidence of a role for NMDA receptors in pain perception | journal = European Journal of Pharmacology | volume = 187 | issue = 3 | pages = 513–8 | date = October 1990 | pmid = 1963598 | doi = 10.1016/0014-2999(90)90379-k }}
• L-687,384: selective for σ₁ subtype (& Spipethiane).
• Lamotrigine{{cite journal | vauthors = Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL, Kusumakar V, Ascher JA, Earl NL, Greene PL, Monaghan ET | title = A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group | journal = The Journal of Clinical Psychiatry | volume = 61 | issue = 11 | pages = 841–50 | date = November 2000 | pmid = 11105737 | doi = 10.4088/jcp.v61n1106 | s2cid = 71423264 }}{{cite journal | vauthors = Ng F, Hallam K, Lucas N, Berk M | title = The role of lamotrigine in the management of bipolar disorder | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 4 | pages = 463–74 | date = August 2007 | pmid = 19300575 | pmc = 2655087 }}
• Memantine:{{cite journal | vauthors = Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E | title = Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine | journal = The European Journal of Neuroscience | volume = 19 | issue = 8 | pages = 2212–20 | date = April 2004 | pmid = 15090047 | doi = 10.1111/j.0953-816X.2004.03297.x | s2cid = 19479968 }} selective for σ₁ subtype, low affinity
• Methamphetamine
• Methylphenidate{{cite journal | vauthors = Zhang CL, Feng ZJ, Liu Y, Ji XH, Peng JY, Zhang XH, Zhen XC, Li BM | title = Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e51910 | year = 2012 | pmid = 23284812 | pmc = 3527396 | doi = 10.1371/journal.pone.0051910 | bibcode = 2012PLoSO...751910Z | doi-access = free }}
• Noscapine{{cite journal | vauthors = Kamei J | title = Role of opioidergic and serotonergic mechanisms in cough and antitussives | journal = Pulmonary Pharmacology | volume = 9 | issue = 5–6 | pages = 349–56 | date = Oct–Dec 1996 | pmid = 9232674 | doi = 10.1006/pulp.1996.0046 }}
• OPC-14523
• Opipramol
• PB-28: selective for σ₂ subtype
• Pentazocine
• Pentoxyverine: selective for σ₁ subtype
• Phencyclidine
• (+)-3-PPP
• PRE-084: selective for σ₁ subtype
• Pregnenolone
• Pregnenolone sulfate
• SA 4503: selective for σ₁ subtype
• Siramesine
• UMB23
• UMB82

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• AC927
• AHD1
• [https://pubchem.ncbi.nlm.nih.gov/compound/58511937 AZ-66]
• BD1008
• BD-1047: selective for σ₁ subtype
• BD1060: selective for σ₁ subtype
• BD1063: selective for σ₁ subtype
• BD1067
• BMY-14802
• CM156: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione{{cite journal | vauthors = Xu YT, Kaushal N, Shaikh J, Wilson LL, Mésangeau C, McCurdy CR, Matsumoto RR | title = A novel substituted piperazine, CM156, attenuates the stimulant and toxic effects of cocaine in mice | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 333 | issue = 2 | pages = 491–500 | date = May 2010 | pmid = 20100904 | pmc = 2872963 | doi = 10.1124/jpet.109.161398 }}
• [https://pubchem.ncbi.nlm.nih.gov/compound/6918385 E-5842]
• Haloperidol
• LR132: selective for σ₁ subtype
• [https://pubchem.ncbi.nlm.nih.gov/compound/5026275 LR172]
• MS-377: selective for σ₁ subtype
• NE-100: selective for σ₁ subtype
• Panamesine
• Phenothiazines{{cite journal | vauthors = Krutetskaya ZI, Melnitskaya AV, Antonov VG, Nozdrachev AD | title = Sigma-1 Receptor Antagonists Haloperidol and Chlorpromazine Modulate the Effect of Glutoxim on Na⁺ Transport in Frog Skin | journal = Doklady. Biochemistry and Biophysics | volume = 484 | issue = 1 | pages = 63–65 | date = May 2019 | pmid = 31012016 | doi = 10.1134/S1607672919010186 | s2cid = 126409347 }}
• Progesterone
• Rimcazole
• S1RA (E-52862): selective for σ₁ subtype
• Sertraline
• UMB 98 & UMB 99{{cite journal |vauthors=Matsumoto RR, Gilmore DL, Pouw B, Bowen WD, Williams W, Kausar A, Coop A |title=Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-induced toxicity in mice |journal=Eur J Pharmacol |volume=492 |issue=1 |pages=21–6 |date=May 2004 |pmid=15145701 |doi=10.1016/j.ejphar.2004.03.037 }}
• [https://pubchem.ncbi.nlm.nih.gov/compound/9971487 UMB100]
• UMB101
• UMB103
• UMB116
• [https://pubchem.ncbi.nlm.nih.gov/compound/10849098 YZ-011]{{cite journal |vauthors=Daniels A, Ayala E, Chen W, Coop A, Matsumoto RR |title=N-[2-(m-methoxyphenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)ethylamine (UMB 116) is a novel antagonist for cocaine-induced effects |journal=Eur J Pharmacol |volume=542 |issue=1-3 |pages=61–8 |date=August 2006 |pmid=16797004 |doi=10.1016/j.ejphar.2006.03.062 }}
• [https://pubchem.ncbi.nlm.nih.gov/compound/401829 YZ-067]{{cite journal |vauthors=Tapia MA, Sage AS, Fullerton EI, Judd JM, Hildebrant PC, Will MJ, Lever SZ, Lever JR, Miller DK |title=The sigma receptor ligand N-phenylpropyl-N'-(4-methoxyphenethyl)3piperazine (YZ-067) enhances the cocaine conditioned-rewarding properties while inhibiting the development of sensitization of cocaine in mice |journal=Psychopharmacology (Berl) |volume=237 |issue=3 |pages=723–734 |date=March 2020 |pmid=31822924 |doi=10.1007/s00213-019-05411-z }}
• [https://pubchem.ncbi.nlm.nih.gov/compound/401827 YZ-069]{{cite journal |vauthors=Matsumoto RR, Potelleret FH, Mack A, Pouw B, Zhang Y, Bowen WD |title=Structure-activity comparison of YZ-069, a novel sigma ligand, and four analogs in receptor binding and behavioral studies |journal=Pharmacol Biochem Behav |volume=77 |issue=4 |pages=775–81 |date=April 2004 |pmid=15099923 |doi=10.1016/j.pbb.2004.01.014 }}
• [https://pubchem.ncbi.nlm.nih.gov/compound/401862 YZ-185]{{cite journal |vauthors=Sage AS, Vannest SC, Fan KH, Will MJ, Lever SZ, Lever JR, Miller DK |title=N-Phenylpropyl-N'-(3-methoxyphenethyl)piperazine (YZ-185) Attenuates the Conditioned-Rewarding Properties of Cocaine in Mice |journal=ISRN Pharmacol |volume=2013 |issue= |pages=546314 |date=2013 |pmid=24089641 |pmc=3780704 |doi=10.1155/2013/546314 |doi-access=free}}

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{{Reflist|2}}

• {{MeshName|sigma+Receptor}}

{{Neuropeptide receptors}}

{{Sigma receptor modulators}}

Category:Receptors