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Sigma-1 receptor 1
Identifikatori
Simboli	SIGMAR1; SRBP; OPRS1; FLJ25585; MGC3851
Vanjski ID	OMIM: 601978 MGI: 1195268 HomoloGene: 39965 GeneCards: SIGMAR1 Gene
Ontologija gena
Molekularna funkcija	• vezivanje leka; • receptorska aktivnost; • aktivnost C-8 sterol izomeraze;
Celularna komponenta	• ćelijska zaštita; • nukleus; • endoplazmatični retikulum; • integralno sa ćelijskom membranom; • nukleusna unutrašnja membrana; • membrana endoplazmatičnog retikuluma; • nukleusna spoljašnja membrana; • ćelijska membrana;
Biološki proces	• lipidni transport; • proces ergosterolne biosinteze;
Ortolozi

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Sigma-1 receptor (σ₁R) je šaperonski protein na endoplazmatičnom retikulumu (ER) koji moduliše kalcijumsku signalizaciju putem IP3 receptora.^[1] Sigma-1 receptor je kod čoveka kodiran SIGMAR1 genom.^[2]^[3]

Sigma-1 receptor je transmembranski protein koji je izražen u mnogim tipovima tkiva. On je posebno koncentrovan u pojedinim regionima centralnog nervnog sistema.^[4] Za njega se smatra da učestvuje u velikom broju sistema, što obuhvata kardiovaskularne funkcije, šizofreniju, kliničku depresiju, efekte zloupotrebe kokaina, i rak.^[5]^[6] Dostupne se detaljne informacije o afinitetu vezivanja stotina sintetičkih jedinjenja za sigma-1 receptor.

Endogeni ligand sigma-1 receptora još uvek nije poznat. Trag amini i halucinogen dimetiltriptamin (DMT), kao i neuroaktivni steroidi poput dehidroepiandrosterona (DHEA) i pregnenolona, mogu da aktiviraju ovaj receptor.^[7]

Struktura

Sigma-1 receptor je integralni membranski protein sa 223 aminokiselina. On nije sličan ni sa jednim drugim poznatim proteinom sisara. On je 30% identičan i 66% homologan sa fungalnom sterol izomerazom, mada nema sposobnost izomeracije sterola.^[8] Hidropatska analiza sigma-1 receptor ukazuje na postojanje tri hidrofobna regiona, i postoji evidencija da postoje dva transmembranska segmenta. Kristalna struktura sigma-1 receptora nije dostupna.

Ligandi

Selektivni ligandi σ1 receptora:

L-687,384
PRE-084: agonist
PD 144418
3-[[1-[(4-hlorofenil)metil]-4-piperidil]metil]-1,3-benzoksazol-2-on: veoma visok afinitet vezivanja i selektivnost^[9]
1'-[(4-fluorofenil)metil]spiro[1H-izobenzofuran-3,4'-piperidin]^[10]
1-benzil-6′-metoksi-6′,7′-dihidrospiro[piperidin-4,4′-tieno[3.2-c]piran]: selektivni antagonist^[11]
1'-benzil-6-metoksi-1-fenil-spiro[6H-furo[3,4-c]pirazol-4,4'-piperidin]^[12]
(−)-(S)-4-metil-1-[2-(4-hlorofenokis)-1-metiletil]piperidin^[13]

Postoji niz liganda koji imaju visok afinitet za σ1 ali im bilo nedostaje σ2 selektivnost ili imaju visok afinitet na druga mesta vezivanja, npr. haloperidol. Postoje i mnogobrojni agensi koji imaju umerenu σ1 aktivnost.^[14]^[15]

Povezano

Literatura

↑ Hayashi T, Su TP (2007). „Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca²⁺ signaling and cell survival.”. Cell 131 (3): 596–610. DOI:10.1016/j.cell.2007.08.036. PMID 17981125.
↑ Kekuda R, Prasad PD, Fei YJ, Leibach FH, Ganapathy V (December 1996). „Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1)”. Biochem. Biophys. Res. Commun. 229 (2): 553–8. DOI:10.1006/bbrc.1996.1842. PMID 8954936.
↑ Prasad PD, Li HW, Fei YJ, Ganapathy ME, Fujita T, Plumley LH, Yang-Feng TL, Leibach FH, Ganapathy V (February 1998). „Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene”. J. Neurochem. 70 (2): 443–51. DOI:10.1046/j.1471-4159.1998.70020443.x. PMID 9453537.
↑ Weissman AD, Su TP, Hedreen JC, London ED (1988). „Sigma receptors in post-mortem human brains”. J. Pharmacol. Exp. Ther. 247 (1): 29–33. PMID 2845055.
↑ Guitart X, Codony X, Monroy X (2004). „Sigma receptors: biology and therapeutic potential”. Psychopharmacology (Berl.) 174 (3): 301–19. DOI:10.1007/s00213-004-1920-9. PMID 15197533.
↑ Zhang H, Cuevas J (2005). „sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons”. J. Pharmacol. Exp. Ther. 313 (3): 1387–96. DOI:10.1124/jpet.105.084152. PMID 15764734.
↑ Fontanilla et al.; Jessett, DM; Brown, CG; Radley, DE; Jackson, M. B.; Ruoho, A. E. (2009). „The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator”. Science 323 (5916): 934–937. DOI:10.1126/science.1166127. PMC 2947205. PMID 19213917.
↑ Su TP, Hayashi T (2003). „Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction”. Curr. Med. Chem. 10 (20): 2073–80. DOI:10.2174/0929867033456783. PMID 12871086.
↑ Zampieri D, Grazia Mamolo M, Laurini E, et al (January 2009). „Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the sigma1 binding site”. Eur J Med Chem 44 (1): 124–30. DOI:10.1016/j.ejmech.2008.03.011. PMID 18440098.
↑ Große Maestrup E, Wiese C, Schepmann D, et al (April 2009). „Synthesis of spirocyclic sigma(1) receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability”. Bioorg. Med. Chem. 17 (10): 3630. DOI:10.1016/j.bmc.2009.03.060. PMID 19394833.
↑ Oberdorf C, Schepmann D, Vela JM, Diaz JL, Holenz J, Wünsch B (October 2008). „Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans]”. J. Med. Chem. 51 (20): 6531–7. DOI:10.1021/jm8007739. PMID 18816044.
↑ Schläger T, Schepmann D, Würthwein EU, Wünsch B (March 2008). „Synthesis and structure-affinity relationships of novel spirocyclic sigma receptor ligands with furopyrazole structure”. Bioorg. Med. Chem. 16 (6): 2992–3001. DOI:10.1016/j.bmc.2007.12.045. PMID 18221879.
↑ Berardi F, Loiodice F, Fracchiolla G, Colabufo NA, Perrone R, Tortorella V (May 2003). „Synthesis of chiral 1-[omega-(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at sigma1, sigma2, and sterol delta8-delta7 isomerase sites”. J. Med. Chem. 46 (11): 2117–24. DOI:10.1021/jm021014d. PMID 12747784.
↑ EP1787679
↑ Lee IT, Chen S, Schetz JA (January 2008). „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”. Eur. J. Pharmacol. 578 (2-3): 123–36. DOI:10.1016/j.ejphar.2007.09.020. PMC 2963108. PMID 17961544.

Vanjske veze

MeSH sigma-1+receptor

[Hayashi-1] Hayashi T, Su TP (2007). „Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca²⁺ signaling and cell survival.”. Cell 131 (3): 596–610. DOI:10.1016/j.cell.2007.08.036. PMID 17981125.

[pmid8954936-2] Kekuda R, Prasad PD, Fei YJ, Leibach FH, Ganapathy V (December 1996). „Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1)”. Biochem. Biophys. Res. Commun. 229 (2): 553–8. DOI:10.1006/bbrc.1996.1842. PMID 8954936.

[pmid9453537-3] Prasad PD, Li HW, Fei YJ, Ganapathy ME, Fujita T, Plumley LH, Yang-Feng TL, Leibach FH, Ganapathy V (February 1998). „Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene”. J. Neurochem. 70 (2): 443–51. DOI:10.1046/j.1471-4159.1998.70020443.x. PMID 9453537.

[pmid2845055-4] Weissman AD, Su TP, Hedreen JC, London ED (1988). „Sigma receptors in post-mortem human brains”. J. Pharmacol. Exp. Ther. 247 (1): 29–33. PMID 2845055.

[pmid15197533-5] Guitart X, Codony X, Monroy X (2004). „Sigma receptors: biology and therapeutic potential”. Psychopharmacology (Berl.) 174 (3): 301–19. DOI:10.1007/s00213-004-1920-9. PMID 15197533.

[pmid15764734-6] Zhang H, Cuevas J (2005). „sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons”. J. Pharmacol. Exp. Ther. 313 (3): 1387–96. DOI:10.1124/jpet.105.084152. PMID 15764734.

[Fontanilla-7] Fontanilla et al.; Jessett, DM; Brown, CG; Radley, DE; Jackson, M. B.; Ruoho, A. E. (2009). „The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator”. Science 323 (5916): 934–937. DOI:10.1126/science.1166127. PMC 2947205. PMID 19213917.

[pmid12871086-8] Su TP, Hayashi T (2003). „Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction”. Curr. Med. Chem. 10 (20): 2073–80. DOI:10.2174/0929867033456783. PMID 12871086.

[pmid18440098-9] Zampieri D, Grazia Mamolo M, Laurini E, et al (January 2009). „Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the sigma1 binding site”. Eur J Med Chem 44 (1): 124–30. DOI:10.1016/j.ejmech.2008.03.011. PMID 18440098.

[pmid19394833-10] Große Maestrup E, Wiese C, Schepmann D, et al (April 2009). „Synthesis of spirocyclic sigma(1) receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability”. Bioorg. Med. Chem. 17 (10): 3630. DOI:10.1016/j.bmc.2009.03.060. PMID 19394833.

[pmid18816044-11] Oberdorf C, Schepmann D, Vela JM, Diaz JL, Holenz J, Wünsch B (October 2008). „Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans]”. J. Med. Chem. 51 (20): 6531–7. DOI:10.1021/jm8007739. PMID 18816044.

[pmid18221879-12] Schläger T, Schepmann D, Würthwein EU, Wünsch B (March 2008). „Synthesis and structure-affinity relationships of novel spirocyclic sigma receptor ligands with furopyrazole structure”. Bioorg. Med. Chem. 16 (6): 2992–3001. DOI:10.1016/j.bmc.2007.12.045. PMID 18221879.

[pmid12747784-13] Berardi F, Loiodice F, Fracchiolla G, Colabufo NA, Perrone R, Tortorella V (May 2003). „Synthesis of chiral 1-[omega-(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at sigma1, sigma2, and sterol delta8-delta7 isomerase sites”. J. Med. Chem. 46 (11): 2117–24. DOI:10.1021/jm021014d. PMID 12747784.

[14] EP1787679

[pmid17961544-15] Lee IT, Chen S, Schetz JA (January 2008). „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”. Eur. J. Pharmacol. 578 (2-3): 123–36. DOI:10.1016/j.ejphar.2007.09.020. PMC 2963108. PMID 17961544.

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Sigma-1 receptor

Struktura

Ligandi

Povezano

Literatura

Vanjske veze

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