Sigma receptors (σ-receptors) are proteinreceptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine),[1]SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine,[2] and siramesine.[3] There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated. Some early literature proposed a third subtype (“sigma-3”) based on phenylaminotetralin (PAT) ligands, but later work showed this binding corresponded to the histamine H1 receptor; “sigma-3” is not recognized in current nomenclature.[4][5][6]
The fungal protein ERG2, a C-8 sterol isomerase, falls into the same protein family as sigma-1. Both localize to the ER membrane, although sigma-1 is also reported to be a cell surface receptor. Sigma-2 is an EXPERA domain protein[7] with a mostly intracellular (ER membrane) localization.[8]
Classification
Because the σ-receptor was originally discovered to be agonized by benzomorphanopioids and antagonized by naltrexone, σ-receptors were originally believed to be a type of opioid receptor.[9] 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.[10] At this point, they were designated as a separate class of proteins.
Putative sigma-3 receptor
In the early 1990s, a “sigma-3” binding site was proposed based on phenylaminotetralin (PAT) ligands and functional assays that linked PAT binding to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain.[4][5] Subsequent pharmacological and radioligand-binding studies demonstrated that these so-called sigma-3 sites correspond to histamine H1 receptors rather than a distinct sigma receptor subtype.[6] As a result, contemporary classifications recognize only sigma-1 and sigma-2 receptors.
Function
The function of these receptors is poorly understood.[11] Drugs known to be σ-agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and berberine.[citation needed] 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. Early rodent studies reported that σ-receptor ligands can functionally antagonize opioid analgesia: (+)-pentazocine and 1,3-di(2-tolyl)guanidine reduced morphine analgesia in a haloperidol-reversible, D2-independent manner, consistent with a tonically active anti-opioid σ1 system.[12][13]
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.[14] Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.[15][16]
In 2007, selective σ-receptor agonists were shown to produce antidepressant-like effects in mice.[17]
σ-receptors were also shown to have a role in the regulation of iron/heme homeostasis.[18]
In mice, σ1 activation attenuated μ-, κ-, and δ-opioid analgesia without altering morphine's effects on gastrointestinal transit or lethality, while σ blockade with haloperidol enhanced analgesia and eliminated strain differences in κ-agonist sensitivity.[13]
^Skuza G, Rogóz Z (June 2006). "The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats". Journal of Physiology and Pharmacology. 57 (2): 217–29. PMID16845227.
^ abMyers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, Booth RG, Wyrick SD (1994-11-25). "Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor". Journal of Medicinal Chemistry. 37 (24): 4109–4117. doi:10.1021/jm00050a008. PMID7990111.
^ abBooth RG, Owens CE, Brown RL, Bucholtz EC, Lawler CP, Wyrick SD (1995-09-15). "1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and related derivatives as ligands for the neuromodulatory sigma-3 receptor: further structure–activity relationships". Journal of Medicinal Chemistry. 38 (19): 3857–3864. doi:10.1021/jm00019a016. PMID7562917.
^ abBooth RG, Owens CE, Brown RL, Bucholtz EC, Lawler CP, Wyrick SD (1999-08-07). "Putative sigma(3) sites in mammalian brain have histamine H(1) receptor properties: evidence from ligand binding and distribution studies with the novel H(1) radioligand [(3)H]-(-)-trans-1-phenyl-3-aminotetralin". Brain Research. 873 (1–2): 95–105. doi:10.1016/s0006-8993(99)01602-9. PMID10433992.
^Kim FJ, Pasternak GW (2017). "Introduction to Sigma Proteins: Evolution of the Concept of Sigma Receptors". Sigma Proteins: Evolution of the Concept of Sigma Receptors. Handbook of Experimental Pharmacology. Vol. 244. Cham: Springer International Publishing. pp. 1–11. doi:10.1007/164_2017_41. ISBN978-3-319-65853-7. PMID28871306.
^Leonard BE (November 2004). "Sigma receptors and sigma ligands: background to a pharmacological enigma". Pharmacopsychiatry. 37 (Suppl 3): S166–70. doi:10.1055/s-2004-832674. PMID15547782. S2CID38914893.
^Chien CC, Pasternak GW (1993-11-30). "Functional antagonism of morphine analgesia by (+)-pentazocine: evidence for an anti-opioid sigma 1 system". European Journal of Pharmacology. 250 (1): R7 –R8. doi:10.1016/0014-2999(93)90650-7. PMID8119306.
^ abChien CC, Pasternak GW (1994). "Selective antagonism of opioid analgesia by a sigma system". Journal of Pharmacology and Experimental Therapeutics. 271 (3): 1583–1590. PMID7996472.
^Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). "Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)". European Neuropsychopharmacology. 7 (1): 25–38. doi:10.1016/S0924-977X(96)00042-9. PMID9088882. S2CID26861697.
^Klepstad P, Maurset A, Moberg ER, Oye I (October 1990). "Evidence of a role for NMDA receptors in pain perception". European Journal of Pharmacology. 187 (3): 513–8. doi:10.1016/0014-2999(90)90379-k. PMID1963598.
^Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E (April 2004). "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". The European Journal of Neuroscience. 19 (8): 2212–20. doi:10.1111/j.0953-816X.2004.03297.x. PMID15090047. S2CID19479968.
^Krutetskaya ZI, Melnitskaya AV, Antonov VG, Nozdrachev AD (May 2019). "Sigma-1 Receptor Antagonists Haloperidol and Chlorpromazine Modulate the Effect of Glutoxim on Na+ Transport in Frog Skin". Doklady. Biochemistry and Biophysics. 484 (1): 63–65. doi:10.1134/S1607672919010186. PMID31012016. S2CID126409347.
^Matsumoto RR, Gilmore DL, Pouw B, Bowen WD, Williams W, Kausar A, Coop A (May 2004). "Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-induced toxicity in mice". Eur J Pharmacol. 492 (1): 21–6. doi:10.1016/j.ejphar.2004.03.037. PMID15145701.
^Daniels A, Ayala E, Chen W, Coop A, Matsumoto RR (August 2006). "N-[2-(m-methoxyphenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)ethylamine (UMB 116) is a novel antagonist for cocaine-induced effects". Eur J Pharmacol. 542 (1–3): 61–8. doi:10.1016/j.ejphar.2006.03.062. PMID16797004.
^Tapia MA, Sage AS, Fullerton EI, Judd JM, Hildebrant PC, Will MJ, Lever SZ, Lever JR, Miller DK (March 2020). "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". Psychopharmacology (Berl). 237 (3): 723–734. doi:10.1007/s00213-019-05411-z. PMID31822924.
^Matsumoto RR, Potelleret FH, Mack A, Pouw B, Zhang Y, Bowen WD (April 2004). "Structure-activity comparison of YZ-069, a novel sigma ligand, and four analogs in receptor binding and behavioral studies". Pharmacol Biochem Behav. 77 (4): 775–81. doi:10.1016/j.pbb.2004.01.014. PMID15099923.
