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

Kompetitivni antagonisti

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

Amantadin: koristi se za tretiranje Parkinsonove bolesti, influenze i Alzheimerove bolesti.^[6]^[7]
Atomoksetin: inhibitor preuzimanja norepinefrina koji se koristi za tretman ADHD.^[8]
AZD6765
Hloroform: jedan od prvih anestetika.
Dekstralorfan: potentniji analog dekstrometorfana.
Dekstrometorfan: antitusik prisutan u lekovima za kašalj.^[9]
Dekstrorfan: aktivni metabolit dekstrometorfana.
Difenidin: dizajnirana droga.^[10]
Dizocilpin (MK-801): eksperimental lek koji se koristi u naučnim istraživanjima.^[11]
Etanol: takođe poznat kao alkohol, široko korišćeni legalni intoksikant.
Eticiklidin: kontrolisana supstanca u SAD.
Gaciklidin: eksperimentalni leki razvijen za neuroprotekciju.
Ibogain: kontrolisana supstanca u SAD.^[12]^[13]
Magnezijum
Memantin: treatment za Alzheimerovu bolest.^[14]
Metoksetamin: dizajnirana droga.
Nitromemantin: derivat memantina.^[15]
Azotsuboksid: koristi se za anesteziju, posebno u zubarstvu.^[16]
Fenciklidin: kontrolisana supstanca u SAD.^[12]
Roliciklidin: kontrolisana supstanca u SAD.
Tenociklidin: kontrolisana supstanca u SAD.
Metoksidin: 4-meo-pcp
Tiletamin: anestetik za životinje.^[17]
Ksenon: anestetik.
Nerameksan: analog memantina sa nootropnim, antidepresantskim svojstvima. Takođe nikotinski acetilholinski antagonist.
Eliprodil: antikonvulsantski lek sa neuroprotektivnim svojstvimia.
Etoksadrol: potentan disocijativ sličan PCP.
Deksoksadrol: sličan etoksadrolu.
WMS-2539: potentan fluorinisani derivat deksoksadrola.^[18]
NEFA: antagonist umerenog afinita.
Remacemid: antagonist niskog afiniteta, takođe blokator natrijumskog kanala.
Delucemin: takođe SSRI s neuroprotektivnim svojstvima.
8A-PDHQ: PCP strukturni analog visokog afiniteta.

Nekompetitivni antagonisti

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

Ovi lekovi deluju na mestu vezivanja glicina:

GLYX-13 (parcijalni agonist)
TK-40 (kompetitivni antagonist GluN1 glicinskog mesta vezivanja)^[22]
1-Aminociklopropan-1-karboksilna kiselina (ACPC)
7-Hlorokinurenska kiselina^[23]
DCKA (5,7-dihlorokinurenska kiselina)^[24]
Kinurenska kiselina: prirodni antagonist^[25]
Lakosamid: lek koji se istražuje za moguću primenu u tretmanu epilepsije i dijabetičkog neuropatičnog bola.^[26]
L-fenilalanin,^[27] prirodna aminokiselina (ravnotežna konstanta disocijacije (K_B je 573 µM)^[28]).

Reference

^ Sun, Lin; Qi Li; Qing Li; Yuzhe Zhang; Dexiang Liu; Hong Jiang; Fang Pan; David T. Yew (12. 11. 2012). „Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys”. Addiction Biology. PMID 23145560. doi:10.1111/adb.12004.
^ Slikker, W.; Zou, X.; Hotchkiss, C. E.; Divine, R. L.; Sadovova, N.; Twaddle, N. C.; Doerge, D. R.; Scallet, A. C.; Patterson, T. A.; Hanig, J. P.; Paule, M. G.; Wang, C. (2007). „Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey”. Toxicological Sciences. 98 (1): 145—158. PMID 17426105. doi:10.1093/toxsci/kfm084.
^ 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. PMC 1618869 . PMID 17060947. doi:10.1172/JCI29867.
^ van den Bos R, Charria Ortiz G, Cools A (1992). „Injections of the NMDA-antagonist D-2-amino-7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enhance switching between cue-directed behaviours in a swimming test procedure”. Behav Brain Res. 48 (2): 165—70. PMID 1535501. doi:10.1016/S0166-4328(05)80153-6.
^ Eblen F, Löschmann P, Wüllner U, Turski L, Klockgether T (1996). „Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions”. Eur J Pharmacol. 299 (1–3): 9—16. PMID 8901001. doi:10.1016/0014-2999(95)00795-4.
^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
^ "MedlinePlus Drug Information: Amantadine." MedlinePlus website Accessed May 29, 2007
^ 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. 5. 2010). „Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations”. British Journal of Pharmacology. стр. 283—291. doi:10.1111/j.1476-5381.2010.00707.x. Приступљено 1. 1. 2014.
^ 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. PMID 2897648. doi:10.1016/0304-3940(88)90362-X.
^ European Patent 0346791 1,2-Diarylethylamines for Treatment of Neurotoxic Injury
^ Fix AS; Horn JW; Wightman KA (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. PMID 8405286. doi:10.1006/exnr.1993.1153.
^ ^а ^б Controlled Substances Act. Accessed from the US Drug Enforcement Administration website Архивирано на сајту Wayback Machine (22. август 2008) on May 29, 2007.
^ Popik, P; Layer, RT; Skolnick, P (1994). „The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex”. Psychopharmacology (Berl). 114 (4): 672—4. PMID 7531855. doi:10.1007/BF02245000.
^ Chawla, PS; MS, Kochar (2006). „What's new in clinical pharmacology and therapeutics”. WMJ. 105 (3): 24—29. PMID 16749321.
^ Talantova, M.; Sanz-Blasco, S.; Zhang, X.; Xia, P.; Akhtar, M. W.; Okamoto, S. -I.; Dziewczapolski, G.; Nakamura, T.; Cao, G.; Pratt, A. E.; Kang, Y. -J.; Tu, S.; Molokanova, E.; McKercher, S. R.; Hires, S. A.; Sason, H.; Stouffer, D. G.; Buczynski, M. W.; Solomon, J. P.; Michael, S.; Powers, E. T.; Kelly, J. W.; Roberts, A.; Tong, G.; Fang-Newmeyer, T.; Parker, J.; Holland, E. A.; Zhang, D.; Nakanishi, N.; Chen, H. -S. V. (2013). „Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss”. Proceedings of the National Academy of Sciences. 110 (27): E2518. PMC 3704025 . PMID 23776240. doi:10.1073/pnas.1306832110.
^ Grasshoff C, Drexler B, Rudolph U, Antkowiak B (2006). „Anaesthetic drugs: linking molecular actions to clinical effects”. Curr. Pharm. Des. 12 (28): 3665—79. PMID 17073666. doi:10.2174/138161206778522038.
^ Ko JC, Smith TA, Kuo WC, Nicklin CF (1998). „Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets”. Journal of the American Animal Hospital Association. 34 (5): 407—16. PMID 9728472.
^ Banerjee A, Schepmann D, Köhler J, Würthwein EU, Wünsch B (2010). „Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists”. Bioorg. Med. Chem. 18 (22): 7855—67. PMID 20965735. doi:10.1016/j.bmc.2010.09.047.
^ Nadler V, Mechoulam R, Sokolovsky M (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. PMID 8121633. doi:10.1016/0304-3940(93)90555-Y.
^ Muir, KW (2005). „Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists”. Current Opinion in Pharmacology. 6 (1): 53—60. PMID 16359918. doi:10.1016/j.coph.2005.12.002.
^ 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. PMC 1987274 . PMID 2858237. doi:10.1111/j.1476-5381.1985.tb12922.x.
^ Kvist, T. „Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site.”. J Biol Chem. (2013). PMID 24072709.
^ Hartley DM, Monyer H, Colamarino SA, Choi DW (1990). „7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture”. Eur J Neurosci. 2 (4): 291—5. PMID 12106035. doi:10.1111/j.1460-9568.1990.tb00420.x.
^ Frankiewicz T, Pilc A, Parsons C (2000). „Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices”. Neuropharmacology. 39 (4): 631—42. PMID 10728884. doi:10.1016/S0028-3908(99)00168-9.
^ Khan MJ, Seidman MD, Quirk WS, Shivapuja BG (2000). „Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig”. Eur Arch Otorhinolaryngol. 257 (4): 177—81. PMID 10867830. doi:10.1007/s004050050218.
^ Prous Science: Molecule of the Month January 2005
^ Glushakov, AV; Dennis, DM; Morey, TE; Sumners, C; Cucchiara, RF; Seubert, CN; Martynyuk, AE (2002). „Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria.”. Molecular psychiatry. 7 (4): 359—67. PMID 11986979. doi:10.1038/sj.mp.4000976.
^ Glushakov, AV; Glushakova, O; Varshney, M; Bajpai, LK; Sumners, C; Laipis, PJ; Embury, JE; Baker, SP; Otero, DH; Dennis, DM; Seubert, CN; Martynyuk, AE (2005). „Long-term changes in glutamatergic synaptic transmission in phenylketonuria.”. Brain: a journal of neurology. 128 (Pt 2): 300—7. PMID 15634735. doi:10.1093/brain/awh354.

[Cynomolgus_monkey_neurotoxiciy-1] Sun, Lin; Qi Li; Qing Li; Yuzhe Zhang; Dexiang Liu; Hong Jiang; Fang Pan; David T. Yew (12. 11. 2012). „Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys”. Addiction Biology. PMID 23145560. doi:10.1111/adb.12004.

[ReferenceA-2] Slikker, W.; Zou, X.; Hotchkiss, C. E.; Divine, R. L.; Sadovova, N.; Twaddle, N. C.; Doerge, D. R.; Scallet, A. C.; Patterson, T. A.; Hanig, J. P.; Paule, M. G.; Wang, C. (2007). „Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey”. Toxicological Sciences. 98 (1): 145—158. PMID 17426105. doi:10.1093/toxsci/kfm084.

[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. PMC 1618869 . PMID 17060947. doi:10.1172/JCI29867.

[4] van den Bos R, Charria Ortiz G, Cools A (1992). „Injections of the NMDA-antagonist D-2-amino-7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enhance switching between cue-directed behaviours in a swimming test procedure”. Behav Brain Res. 48 (2): 165—70. PMID 1535501. doi:10.1016/S0166-4328(05)80153-6.

[5] Eblen F, Löschmann P, Wüllner U, Turski L, Klockgether T (1996). „Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions”. Eur J Pharmacol. 299 (1–3): 9—16. PMID 8901001. doi:10.1016/0014-2999(95)00795-4.

[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

[7] "MedlinePlus Drug Information: Amantadine." MedlinePlus website Accessed May 29, 2007

[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. 5. 2010). „Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations”. British Journal of Pharmacology. стр. 283—291. doi:10.1111/j.1476-5381.2010.00707.x. Приступљено 1. 1. 2014.

[wong-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. PMID 2897648. doi:10.1016/0304-3940(88)90362-X.

[10] European Patent 0346791 1,2-Diarylethylamines for Treatment of Neurotoxic Injury

[11] Fix AS; Horn JW; Wightman KA (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. PMID 8405286. doi:10.1006/exnr.1993.1153.

[CSA-12] а ^б Controlled Substances Act. Accessed from the US Drug Enforcement Administration website Архивирано на сајту Wayback Machine (22. август 2008) on May 29, 2007.

[13] Popik, P; Layer, RT; Skolnick, P (1994). „The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex”. Psychopharmacology (Berl). 114 (4): 672—4. PMID 7531855. doi:10.1007/BF02245000.

[Chawla-14] Chawla, PS; MS, Kochar (2006). „What's new in clinical pharmacology and therapeutics”. WMJ. 105 (3): 24—29. PMID 16749321.

[15] Talantova, M.; Sanz-Blasco, S.; Zhang, X.; Xia, P.; Akhtar, M. W.; Okamoto, S. -I.; Dziewczapolski, G.; Nakamura, T.; Cao, G.; Pratt, A. E.; Kang, Y. -J.; Tu, S.; Molokanova, E.; McKercher, S. R.; Hires, S. A.; Sason, H.; Stouffer, D. G.; Buczynski, M. W.; Solomon, J. P.; Michael, S.; Powers, E. T.; Kelly, J. W.; Roberts, A.; Tong, G.; Fang-Newmeyer, T.; Parker, J.; Holland, E. A.; Zhang, D.; Nakanishi, N.; Chen, H. -S. V. (2013). „Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss”. Proceedings of the National Academy of Sciences. 110 (27): E2518. PMC 3704025 . PMID 23776240. doi:10.1073/pnas.1306832110.

[16] Grasshoff C, Drexler B, Rudolph U, Antkowiak B (2006). „Anaesthetic drugs: linking molecular actions to clinical effects”. Curr. Pharm. Des. 12 (28): 3665—79. PMID 17073666. doi:10.2174/138161206778522038.

[17] Ko JC, Smith TA, Kuo WC, Nicklin CF (1998). „Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets”. Journal of the American Animal Hospital Association. 34 (5): 407—16. PMID 9728472.

[18] Banerjee A, Schepmann D, Köhler J, Würthwein EU, Wünsch B (2010). „Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists”. Bioorg. Med. Chem. 18 (22): 7855—67. PMID 20965735. doi:10.1016/j.bmc.2010.09.047.

[19] Nadler V, Mechoulam R, Sokolovsky M (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. PMID 8121633. doi:10.1016/0304-3940(93)90555-Y.

[Muir-20] Muir, KW (2005). „Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists”. Current Opinion in Pharmacology. 6 (1): 53—60. PMID 16359918. doi:10.1016/j.coph.2005.12.002.

[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. PMC 1987274 . PMID 2858237. doi:10.1111/j.1476-5381.1985.tb12922.x.

[22] Kvist, T. „Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site.”. J Biol Chem. (2013). PMID 24072709.

[23] Hartley DM, Monyer H, Colamarino SA, Choi DW (1990). „7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture”. Eur J Neurosci. 2 (4): 291—5. PMID 12106035. doi:10.1111/j.1460-9568.1990.tb00420.x.

[24] Frankiewicz T, Pilc A, Parsons C (2000). „Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices”. Neuropharmacology. 39 (4): 631—42. PMID 10728884. doi:10.1016/S0028-3908(99)00168-9.

[pmid10867830-25] Khan MJ, Seidman MD, Quirk WS, Shivapuja BG (2000). „Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig”. Eur Arch Otorhinolaryngol. 257 (4): 177—81. PMID 10867830. doi:10.1007/s004050050218.

[26] Prous Science: Molecule of the Month January 2005

[27] Glushakov, AV; Dennis, DM; Morey, TE; Sumners, C; Cucchiara, RF; Seubert, CN; Martynyuk, AE (2002). „Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria.”. Molecular psychiatry. 7 (4): 359—67. PMID 11986979. doi:10.1038/sj.mp.4000976.

[28] Glushakov, AV; Glushakova, O; Varshney, M; Bajpai, LK; Sumners, C; Laipis, PJ; Embury, JE; Baker, SP; Otero, DH; Dennis, DM; Seubert, CN; Martynyuk, AE (2005). „Long-term changes in glutamatergic synaptic transmission in phenylketonuria.”. Brain: a journal of neurology. 128 (Pt 2): 300—7. PMID 15634735. doi:10.1093/brain/awh354.

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