Antagonist NMDA receptora

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Ketamin, prototipni antagonist NMDA receptora.

Antagonisti NMDA receptora su klasa anestetika koji antagonizuju, ili inhibiraju dejstvo, N-metil-D-aspartatnog receptora (NMDAR). Oni se koriste kao anestetici za životinje i ljude. Stanje anestezije koje oni indukuju se naziva disocijativna anestezija. Postoji evidencija da antagonisti NMDA receptora mogu da uzrokuju određene tipove neurotoksičnosti ili oštećenja mozga koja se nazivaju Olnejeve ozlede kod glodara, mada takva oštećenja nikad nisu bila ubedljivo zapažena kod primata poput čoveka. Nedavna istraživanja na primatima sugerišu da dok veoma konzistentna i dugotrajna upotreba ketamina može da bude neurotoksična, akutna primena nije.[1][2]

Nekoliko sintetičkih opioida dodatno deluju kao NMDAR antagonisti, npr. petidin, metadon, dekstropropoksifen, tramadol i ketobemidon.

Neki antagonisti NMDA receptora, kao što su ketamin, dekstrometorfan (DXM), fenciklidin (PCP), i azot-monoksid (N2O), su popularne rekreacione droge koje se koriste zbog njihovih disocijativnih, halucinogenih, i euforijantnih svojstava.

Primeri[uredi | uredi kod]

Kompetitivni antagonisti[uredi | uredi kod]

  • AP5 (APV, R-2-amino-5-fosfonopentanoat)[3]
  • AP7 (2-amino-7-fosfonoheptanska kiselina)[4]
  • Midafotel (3-[(R)-2-karboksipiperazin-4-il]-prop-2-enil-1-fosfonska kiselina)[5]
  • Selfotel: anksiolitik, antikonvulsant sa mogućim neurotoksičnim destvom.

Nekompetitivni blokatori kanala[uredi | uredi kod]

Nekompetitivni antagonisti[uredi | uredi kod]

  • Aptiganel (Cerestat, CNS-1102): vezuje se za mestove vezivanja Mg2+ u kanalu NMDA receptora.
  • HU-211: enantiomer potentnog kanabinoida HU-210 koji nema kanabinoidno dejstvo već deluje kao potentan nekompetitivni NMDA antagonist.[19]
  • Remacemid: glavni metabolit nekompetitivnog antagonista sa niskim afinitetom za mestom vezivanja.[20]
  • Rinhofilin, alkaloid.
  • Ketamin: disocijativni psihodelik sa antidepresantskim svojstvima koji se koristi za anasteziju kod ljudi i životinja[21]

Glicinski antagonisti[uredi | uredi kod]

Ovi lekovi deluju na mestu vezivanja glicina:

Reference[uredi | uredi kod]

  1. Sun, Lin; Qi Li, Qing Li, Yuzhe Zhang, Dexiang Liu, Hong Jiang, Fang Pan, David T. Yew (12 November 2012). „Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys”. Addiction Biology. DOI:10.1111/adb.12004. PMID 23145560. 
  2. DOI:10.1093/toxsci/kfm084
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  3. Abizaid A, Liu Z, Andrews Z, Shanabrough M, Borok E, Elsworth J, Roth R, Sleeman M, Picciotto M, Tschöp M, Gao X, Horvath T (2006). „Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite”. J Clin Invest 116 (12): 3229–39. DOI:10.1172/JCI29867. PMC 1618869. PMID 17060947. 
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  6. "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
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  8. Ludolph, Andrea G; Udvardi, Patrick T; Schaz, Ulrike; Henes, Carolin; Adolph, Oliver; Weigt, Henry U; Fegert, Joerg M; Boeckers, Tobias M; Föhr, Karl J (1 May 2010). „Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations”. British Journal of Pharmacology. str. 283–291. DOI:10.1111/j.1476-5381.2010.00707.x. Pristupljeno 1 January 2014. 
  9. Wong BY, Coulter DA, Choi DW, Prince DA (1988). „Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices”. Neurosci. Lett. 85 (2): 261–6. DOI:10.1016/0304-3940(88)90362-X. PMID 2897648. 
  10. European Patent 0346791 1,2-Diarylethylamines for Treatment of Neurotoxic Injury
  11. Fix AS, Horn JW, Wightman KA, et al. (1993). „Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex”. Exp. Neurol. 123 (2): 204–15. DOI:10.1006/exnr.1993.1153. PMID 8405286. 
  12. 12,0 12,1 Controlled Substances Act. Accessed from the US Drug Enforcement Administration website on May 29, 2007.
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  14. Chawla, PS; Kochar MS (2006). „What's new in clinical pharmacology and therapeutics”. WMJ 105 (3): 24–29. PMID 16749321. 
  15. DOI:10.1073/pnas.1306832110
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  18. Banerjee A, Schepmann D, Köhler J, Würthwein EU, Wünsch B (November 2010). „Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists”. Bioorg. Med. Chem. 18 (22): 7855–67. DOI:10.1016/j.bmc.2010.09.047. PMID 20965735. 
  19. Nadler V, Mechoulam R, Sokolovsky M (November 1993). „The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6- tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-D-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain”. Neurosci. Lett. 162 (1–2): 43–5. DOI:10.1016/0304-3940(93)90555-Y. PMID 8121633. 
  20. Muir, KW (2005). „Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists”. Current Opinion in Pharmacology 6 (1): 53–60. DOI:10.1016/j.coph.2005.12.002. PMID 16359918. 
  21. Harrison N, Simmonds M (1985). „Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex”. Br J Pharmacol 84 (2): 381–91. DOI:10.1111/j.1476-5381.1985.tb12922.x. PMC 1987274. PMID 2858237. 
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