5-HT2A receptor

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5-hidroksitriptaminski (serotoninski) receptor 2A
Identifikatori
Simboli HTR2A; 5-HT2A; HTR2
Vanjski ID OMIM182135 MGI109521 HomoloGene68073 GeneCards: HTR2A Gene
Pregled RNK izražavanja
PBB GE HTR2A 207135 at tn.png
PBB GE HTR2A 211616 s at tn.png
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 3356 15558
Ensembl ENSG00000102468 ENSMUSG00000034997
UniProt P28223 Q543D4
RefSeq (mRNA) NM_000621 NM_172812.2
RefSeq (protein) NP_000612 NP_766400.1
Lokacija (UCSC) Chr 13:
47.41 - 47.47 Mb
Chr 14:
75.04 - 75.11 Mb
PubMed pretraga [1] [2]

Sisarski 5-HT2A receptor je tip 5-HT2 receptora koji pripada serotoninskoj receptorskoj familiji G protein-spregnutih receptor (GPCR).[1] To je glavni pobuđivački receptorski tip među GPCR receptorima serotonina (5-HT), mada 5-HT2A može takođe da ima inhibitorno dejstvo[2] u pojedinim oblastima kao što je vizuelni korteks i orbitofrontalni korteks. Ovaj receptor inicijalno zadobio značaj kao meta psihedeličnih droga poput LSD. Kasnije je utvrđeno da delimično posreduje dejstvo mnogih antipsihotičkih lekova, posebno grupe atipičnih antipsihotika.

5-HT2A receptor je isto tako neophodan za širenje humanog polioma virusa poznatog kao JC virus.[3]

Istorija[uredi - уреди]

Serotoninski receptori su podeljeni u dve klase od strane Gaduma i Pikarelija nakon što je utvrđeno da neke od serotoninom indukovanih promena u crevima mogu da budu blokirane morfinom, dok se preostali mogu inhibirati dibenzilinom. Dve grupe su nazvane M i D receptori. Za 5-HT2A se mislilo da je receptor D grupe 5-HT receptora.[4] U periodu pre molekularnog kloniranja, kada je vezivanje radioliganda i njegovo zamenjivanje bilo jedino oruđe, za spiperon i LSD je pokazano da obeležavaju dva različita serotoninska receptora, i da nijedan od njih ne zamenjuje morfin. Na osnovu toga su izvedena imena 5-HT1, 5-HT2 i 5-HT3 receptori, koji korespondiraju visokom afinitetu za LSD, spiperon i morfin.[5] Kasnije je pokazano da je 5-HT2 veoma sličan sa 5-HT1C tako da su grupisani u istu grupu, i 5-HT2 je preimenovan u 5-HT2A. Stoga se 5-HT2 receptorska familija sastoji od tri zasebne molekulske grupe: 5-HT2A (nekada 5-HT2 ili D), 5-HT2B (nekada 5-HT2F) i 5-HT2C (nekada 5-HT1C).[6]

Distribucija[uredi - уреди]

5-HT2A je u znatnoj meri izražen širom centralnog nervnog sistema (CNS). Posebno visoke koncentracije ovog receptora su nađene u apikalnim dendritima piramidalnih ćelija u sloju V korteksa gde moduliraju kognitivne procese,[7][8][9] uvećavanjem glutamatnog otpuštanja nakon kompleksnog skupa interakcija sa 5-HT1A,[10] GABAA,[11] adenozinskim A1,[12] AMPA,[13] mGluR2/3,[14] mGlu5,[15] i OX2 receptorima.[16][17] U malom mozgu pacova, ovaj protein je isto tako nađen u Goldžijevim ćelijama granularnog sloja,[18] i u Purkinje ćelijama.[19][20]

Na periferiji, on je visoko izražen u trombocitima, i u više ćelijskih tipova kardiovaskularnog sistema, u fibroblastima, i u neuronima perifernog nervnog sistema. Osim toga, 5-HT2A iRNK izražavanje je primećeno u humanim monocitima.[21]

Efekti[uredi - уреди]

Fiziološki procesi posredovani ovim receptorom su:

Ligandi[uredi - уреди]

Agonisti[uredi - уреди]

Aktivacija 5-HT2A receptora je neophodna za dejstvo „klasičnih“ psihodelika kao što su LSD, psilocin i meskalin, koji deluju kao puni ili parcijalni agonisti ovog receptora, i predstavljaju tri glavne klase 5-HT2A agonista, ergolina, triptamina i fenetilamina, respektivno. Veoma velika familija derivata iz ove tri klase je razvijena, i njihovi odnosi strukture i aktivnosti su ekstenzivno istraženi.[23][24] Za agoniste koji deluju na 5-HT2A receptore locirane na apikalnim dendritima piramidalnih ćelija unutar regiona prefrontalnog korteksa se veruje da posreduje halucinogenu aktivnost.

Puni agonisti[uredi - уреди]

Parcijalni agonisti[uredi - уреди]

Metisergid, koji je srodan sa metilergonovinom, se koristi za lečenje migrene. On blokira 5-HT2A i 5-HT2C receptore. Atipični antipsihotik aripiprazol je isto tako slab parcijalni agonist.[28]

Antagonisti[uredi - уреди]

  • Mada su ergot alkaloidi uglavnom nespecifični antagonisti 5-HT receptora, nekoliko ergot derivata kao što je metergolin se vezuju preferentno za članove 5-HT2 receptorske familije.
  • Ketanserin, prototipski antagonist 5-HT2 receptora potentno blokira 5-HT2Areceptore, manje potentno blokira 5-HT2C receptore, i nema uticaja na 5-HT3 ili 5-HT4 receptore ili bilo koji član 5-HT1 receptorske familije.[29] Otkriće ovakvog profila ketanserina je bila prekretnica u farmakologiji 5-HT2 receptora. Mada ketanserin može da blokira 5-HT indukovanu adheziju trombocita, on ne vrši svoje antihipertenzivno dejstvo putem 5-HT2 receptora, nego je to posledica njegovog visokog afiniteta za alfa1 adrenergičke receptore. On takođe ima visok afinitet za H1 histaminergičke receptore. Jedinjenja koja su hemijski srodna sa ketanserinom kao što je ritanserin su selektivniji antagonisti 5-HT2A receptor sa manjim afinitetom za alfa-adrenergičke receptore. Međutim, ritanserin, poput većine drugih 5-HT2A antagonista, isto tako potentno inhibira 5-HT2C receptore.
  • Nefazodon deluje putem blokiranja post-sinaptičkog serotoninskog 2A receptora i u manjoj meri inhibiranjem pre-sinaptičkog serotonin i norepinefrin (noradrenalin) preuzimanja.
  • 2-alkil-4-arol-tetrahidro-pirimido-azepini su tip selektivnih antagonista.[31]

Inverse agonists[uredi - уреди]

  • Nelotanserin (APD-125) - selektivni 5-HT2A inverzni agonist razvijen za tretman insomnije. Za APD-125 je pokazano u kliničkim ispitivanjima da je efektivan i dobro tolerisan,[39] ali je dalji razvoj zaustavljen 2008 zato što supstanca zadovoljile kriterijume ispitivanja.[40]
  • Eplivanserin (Sanofi Aventis), pilula za spavanje koja je dospela do ispitivanja faze II, ali je aplikacija za odobrenje povučena. On deluje kao selektivni 5-HT2A inverzni agonist.

Primeri[uredi - уреди]

Agonisti Antagonisti

Vidi još[uredi - уреди]

Reference[uredi - уреди]

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  40. APD125 for Insomnia
  41. Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE (May 2006). "Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist". J. Pharmacol. Exp. Ther. 317 (2): 910–8. doi:10.1124/jpet.105.097006. PMID 16469866. 
  42. Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (August 2007). "ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models". J. Pharmacol. Exp. Ther. 322 (2): 862–70. doi:10.1124/jpet.107.121715. PMID 17519387. 
  43. Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (October 2008). "A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model". Pharmacol. Biochem. Behav. 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670. PMID 18534670. 
  44. Abbas A, Roth BL (December 2008). "Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders". Expert Opin Pharmacother 9 (18): 3251–9. doi:10.1517/14656560802532707. PMID 19040345. 

Literatura[uredi - уреди]

Spoljašnje veze[uredi - уреди]