Epilepsy Research
Volume 69, Issue 3 , Pages 273-294 , June 2006

Diverse mechanisms of antiepileptic drugs in the development pipeline

Received 29 November 2005 ,Revised 12 February 2006 ,Accepted 12 February 2006.

References 

  1. Abou-Khalil B, Porter RJ, Nohria V. Safety and tolerability of different titration rates of the novel AED retigabine. Epilepsia. 2004;45(Suppl. 7):(2.356)
  2. Almeida L, Falcao A, Maia J, Mazur D, Gellert M, Soares-da-Silva P. Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy elderly and young subjects. J. Clin. Pharmacol. 2005;45:1062–1066
  3. Ambrósio AF, Silva AP, Malva JO, Soares-da-Silva P, Carvalho AP, Carvalho CM. Inhibition of glutamate release by BIA 2-093 and BIA 2-024, two novel derivatives of carbamazepine, due to blockade of sodium but not calcium channels. Biochem. Pharmacol. 2001;61:1271–1275
  4. Andrási F. Talampanel. Drugs Fut. 2001;26:754–756
  5. Asano T, Mori T, Shimoda T, Shinagawa R, Satoh S, Yada N, et al. Arundic acid (ONO-2506) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of S100B. Curr. Drug Targets CNS Neurol. Disord. 2005;4:127–142
  6. Atack JR, Wafford K, Tye SJ, Cook S, Sohal B, Pike A, et al. TPA023, an agonist selective for α2- and α3-containing GABAA receptors, is a non-sedating anxiolytic in rodents and primates. J. Pharmacol. Exp. Ther. 2006;316:410–422
  7. Barel S, Yagen B, Schurig V, Soback S, Pisani F, Perucca E, et al. Stereoselective pharmacokinetic analysis of valnoctamide in healthy subjects and in patients with epilepsy. Clin. Pharmacol. Ther. 1997;61:442–449
  8. Barton ME, Klein BD, Wolf HH, White HS. Pharmacological characterization of the 6Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 2001;47:217–227
  9. Barton ME, Peters SC, Shannon HE. Comparison of the effect of glutamate receptor modulators in the 6Hz and maximal electroshock seizure models. Epilepsy Res. 2003;56:17–26
  10. Béguin C, Andurkar SV, Jin AY, Stables JP, Weaver DF, Kohn H. Functionalized amido ketones: new anticonvulsant agents. Bioorg. Med. Chem. 2003;11:4275–4285
  11. Béguin C, LeTiran A, Stables JP, Voyksner RD, Kohn H. N-Substituted amino acid N’-benzylamides: synthesis, anticonvulsant, and metabolic activities. Bioorg. Med. Chem. 2004;12:3079–3096
  12. Benes J, Parada A, Figueiredo AA, Alves PC, Freitas AP, Learmonth DA, et al. Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J. Med. Chem. 1999;42:2582–2587
  13. Bialer M. Clinical pharmacology of valpromide. Clin. Pharmacokinet. 1991;20:114–122
  14. Bialer M, Haj-Yehia A, Barzaghi N, Pisani F, Perucca E. Pharmacokinetics of a valpromide isomer, valnoctamide, in healthy subjects. Eur. J. Clin. Pharmacol. 1990;38:289–291
  15. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: a summary of the Fifth Eilat Conference (EILAT V). Epilepsy Res. 2001;43:11–58
  16. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress report on new anti epileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res. 2004;61:1–48
  17. Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE. Retigabine: chemical synthesis to clinical application. CNS Drug Rev. 2005;11:1–20
  18. Blotnick S, Bergman F, Bialer M. Disposition of valpromide, valproic acid and valnoctamide in the brain, liver, plasma and urine of rats. Drug Metab. Dispos. 1996;24:560–564
  19. Bonifácio MJ, Sheridan RD, Parada A, Cunha RA, Patmore L, Soares-da-Silva P. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia. 2001;42:600–608
  20. Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, et al. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ-aminobutyric acidA receptor. J. Pharmacol. Exp. Ther. 1997;280:1284–1295
  21. Chappell AS, Sander JW, Brodie MJ, Chadwick D, Lledo A, Zhang D, et al. A crossover, add-on trial of talampanel in patients with refractory partial seizures. Neurology. 2002;58:1680–1682
  22. Choi D, Stables JP, Kohn H. Synthesis and anticonvulsant activities of N-benzyl-2-acetamidopropionamide derivatives. J. Med. Chem. 1996;39:1907–1916
  23. Choi, Y.M., Kim, M.W., Park, J., 1997. Halogen substituted carbamate compounds from 2-phenyl-1,2-ethanediol. U.S. Patent 5,698,588, December 16, 1997.
  24. Choi, Y.M., Kim, M.W., Park. J., 2000. Halogen substituted carbamate compounds from 2-phenyl-1,2-ethanediol. U.S. Patent 6,103,759, August 15, 2000.
  25. Conley JD, Kohn H. Functionalized dl-amino acid derivatives potent new agents for the treatment of epilepsy. J. Med. Chem. 1987;30:567–574
  26. Cortes S, Liao ZK, Watson D, Kohn H. Effect of structural modification of the hydantoin ring on anticonvulsant activity. J. Med. Chem. 1985;28:601–606
  27. Costa E, Guidotti A. Benzodiazepines on trial: a research strategy for their rehabilitation. Trends Pharmacol. Sci. 1996;17:192–200
  28. Crestani F, Martin JR, Möhler H, Rudolph U. Mechanism of action of the hypnotic zolpidem in vivo. Br. J. Pharmacol. 2000;131:1251–1254
  29. Danielsson I, Su K, Kauer L, Barnette L, Reeves-Tyer P, Kelley K, et al. Talampanel and human cortical excitability: EEG and TMS.. Epilepsia. 2004;45(Suppl. 7):120;(1.314)
  30. de Paulis T. ONO-2506. Curr. Opin. Investig. Drugs. 2003;4:863–867
  31. Delmas P, Brown DA. Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat. Rev. Neurosci. 2005;6:850–862
  32. Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, et al. Zolpidem, a novel nonbenzodiazepine hypnotic I. Neuropharmacological and behavioral effects. J. Pharmacol. Exp. Ther. 1986;237:649–658
  33. Donevan SD, Rogawski MA. GYKI 52466 a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses. Neuron. 1993;10:51–59
  34. Dost, R., Langen, B., Rundfeldt, C., 2005. The α-3 subunit selective benzodiazepine agonist ELB139 does not induce tolerance in animal models for anxiety and epilepsy. Soc. Neurosci. Abst., Program No. 678.1.
  35. Dubinsky B, Vaidya AH, Rosenthal DI, Hochman C, Crooke JJ, DeLuca S, et al. 5-Ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2a]pyridine-4-N-(2-fluorophenyl)carboxamide (RWJ-51204), a new nonbenzodiazepine anxiolytic. J. Pharmacol. Exp. Ther. 2002;303:777–790
  36. Eadie MJ. Could valerian have been the first anticonvulsant?. Epilepsia. 2004;45:1338–1343
  37. Faigle JW, Menge GP. Metabolic characteristics of oxcarbazepine and their clinical significance: comparison with carbamazepine. Behav. Neurol. 1990;3(suppl 1):21–30
  38. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 2005;6:215–229
  39. Francois J, Ferrandon A, Koning E, Nehlig A. A new drug RWJ 333369 protects limbic areas in the lithium-pilocarpine model (li-pilo) of epilepsy and delays or prevents the occurrence of spontaneous seizures. Epilepsia. 2005;46(Suppl. 8):269–270(C.04)
  40. Gower AJ, Hirsch E, Boehrer A, Noyer M, Marescaux C. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. Epilepsy Res. 1995;22:207–213
  41. Gower AJ, Noyer M, Verloes R, Gobert J, Wulfert E. ucb L059, a novel anti-convulsant drug: pharmacological profile in animals. Eur. J. Pharmacol. 1992;222:193–203
  42. Grabenstatter HL, Dudek FE. The use of chronic models in antiepileptic drug discovery: the effect of RWJ-333369 on spontaneous motor seizures in rats with kainate-induced epilepsy. Epilepsia. 2004;45(Suppl. 7):197;(2.016)
  43. Hamilton NM. Interaction of steroids with the GABAA receptor. Curr. Top. Med. Chem. 2002;2:887–902
  44. Harty TP, Rogawski MA. Felbamate block of recombinant N-methyl-d-aspartate receptors: selectivity for the NR2B subunit. Epilepsy Res. 2000;39:47–55
  45. Herzog AG. Progesterone therapy in women with complex partial and secondary generalized seizures. Neurology. 1995;45:1660–1662
  46. Holmes GL. Carbamazepine adverse effects. In:  Levy RH,  Mattson RH,  Meldrum BS,  Perucca E editor. Antiepileptic Drugs. Philadelphia: Lippincott-Raven; 2002;p. 284–297
  47. Hovinga CA. SPM-927 (Schwarz Pharma). IDrugs. 2003;6:479–485
  48. Hovinga CA. Valrocemide (Teva/Acorda). Curr. Opin. Investig. Drugs. 2004;5:101–106
  49. Isoherranen N, White HS, Klein BD, Roeder M, Woodhead JH, Schurig V, et al. Pharmacokinetic–pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R 3S)-valnoctamide in rodent models of epilepsy. Pharm. Res. 2003;20:1293–1301
  50. Isoherranen N, Woodhead JH, White HS, Bialer M. Anticonvulsant profile of valrocemide (TV1901): a new antiepileptic drug. Epilepsia. 2001;42:831–836
  51. Isoherranen N, Yagen B, Bialer M. New CNS-active drugs which are second-generation valproic acid: can they lead to the development of a magic bullet?. Curr. Opin. Neurol. 2003;16:203–211
  52. Isoherranen N, Yagen B, Woodhead JH, Spiegelstein O, Blotnik S, Wilcox KS, et al. Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents. Br. J. Pharmacol. 2003;138:602–613
  53. Janz R, Goda Y, Geppert M, Missler M, Südhof TC. SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron. 1999;24:1003–1016
  54. Jentsch TJ. Neuronal KCNQ potassium channels: physiology and role in disease. Nat. Rev. Neurosci. 2000;1:21–30
  55. Johnstone TB, Hogenkamp DJ, Coyne L, Su J, Halliwell RF, Tran MB, et al. Modifying quinolone antibiotics yields new anxiolytics. Nat. Med. 2004;10:31–32
  56. Kaminski RM, Livingood MR, Rogawski MA. Allopregnanolone analogs that positively modulate GAB A receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice. Epilepsia. 2004;45:864–867
  57. Karolchyk MA, Schmidt D. Drugs in development rufinamide. In:  Levy RH,  Mattson RH,  Meldrum BS,  Perucca E editor. Antiepileptic Drugs. Philadelphia: Lippincott-Raven; 2002;p. 906–912
  58. Kasteleijn-Nolst Trenitè DG, Parain D, Masnou P, Genton P, Steinhoff BJ, Hirsch E. Proof of principle in the new AED UCB 34714 Use of the photosensitivity model. Epilepsia. 2004;45(Suppl. 7):309;(2.346)
  59. Kenda BM, Matagne AC, Talaga PE, Pasau PM, Differding E, Lallemand BI, et al. Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J. Med. Chem. 2004;47:530–549
  60. Kleckner NW, Glazewski JC, Chen CC, Moscrip TD. Subtype-selective antagonism of N-methyl-d-aspartate receptors by felbamate: insights into the mechanism of action. J. Pharmacol. Exp. Ther. 1999;289:886–894
  61. Kleckner NW, Glazewski JC, Chen CC, Moscrip TD. Subtype-selective antagonism of N-methyl-d-aspartate receptors by felbamate: insights into the mechanism of action. J. Pharmacol. Exp. Ther. 1999;289:886–894
  62. Klitgaard H. Levetiracetam: the preclinical profile of a new class of antiepileptic drugs?. Epilepsia. 1999;42(Suppl. 4):13–18
  63. Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur. J. Pharmacol. 1998;353:191–206
  64. Kokate TG, Banks MK, Magee T, Yamaguchi S, Rogawski MA. Finasteride, a 5α-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice. J. Pharmacol. Exp. Ther. 1999;288:679–684
  65. Kokate TG, Cohen AL, Karp E, Rogawski MA. Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice. Neuropharmacology. 1996;35:1049–1056
  66. Kokate TG, Svensson BE, Rogawski MA. Anticonvulsant activity of neurosteroids: correlation with γ-aminobutyric acid-evoked chloride current potentiation. J. Pharmacol. Exp. Ther. 1994;270:1223–1229
  67. Kokate TG, Yamaguchi S, Pannell LK, Rajamani U, Carroll DM, Grossman AB, et al. Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. J. Pharmacol. Exp. Ther. 1998;287:553–558
  68. Kralic JE, Korpi ER, O’Buckley TK, Homanics GE, Morrow AL. Molecular and pharmacological characterization of GABAA receptor α1 subunit knockout mice. J. Pharmacol. Exp. Ther. 2002;302:1037–1045
  69. Kume A, Greenfield LJ, Macdonald RL, Albin RL. Felbamate inhibits [3H]t-butylbicycloorthobenzoate (TBOB) binding and enhances Cl− current at the γ-aminobutyric acidA (GABAA) receptor. J. Pharmacol. Exp. Ther. 1996;277:1784–1792
  70. Kuo CC, Lin BJ, Chang HR, Hsieh CP. Use-dependent inhibition of the N-methyl-d-aspartate currents by felbamate: a gating modifier with selective binding to the desensitized channels. Mol. Pharmacol. 2004;65:370–380
  71. Lambert JJ, Belelli D, Harney SC, Peters JA, Frenguelli BG. Modulation of native and recombinant GABAA receptors by endogenous and synthetic neuroactive steroids. Brain Res. Brain Res. Rev. 2001;37:68–80
  72. Langan YM, Lucas R, Jewell H, Toublanc N, Schaefer H, Sander JW, et al. Talampanel, a new antiepileptic drug: single- and multiple-dose pharmacokinetics and initial 1-week experience in patients with chronic intractable epilepsy. Epilepsia. 2003;44:46–53
  73. Langen B, Egerland U, Bernoster K, Dost R, Unverferth K, Rundfeldt C. Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor. J. Pharmacol. Exp. Ther. 2005;314:717–724
  74. Langen, B., Rundfeldt, C., Dost, R., Luddens, H., Rabe, H., 2004. Method of treating or preventing central nervous system disorders with compounds having selectivity for the alpha3 subunit of the benzodiazepine receptor. U.S. Patent Application 20,050,032,863.
  75. Lees G, Stohr T, Errington AC. Stereoselective effects of the novel anti con vulsant lacosamide against 4-AP induced epileptiform activity in rat visual cortex in vitro. Neuropharmacology. 2006;50:98–110
  76. Löscher W. Valproic acid mechanisms of action. In:  Levy RH,  Mattson RH,  Meldrum BS,  Perucca E editor. Antiepileptic Drugs. Philadelphia: Lippincott-Raven; 2002;p. 768–779
  77. Löscher W, Hönack D. Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. Eur. J. Pharmacol. 1993;232:147–158
  78. Löscher W, Honack D. Effects of the non-NMDA antagonists NBQX and the 2,3-benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil. Br. J. Pharmacol. 1994;113:1349–1357
  79. Löscher W, Honack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 1998;284:474–479
  80. Löscher W, Nau H. Pharmacological evaluation of various metabolites and analogues of valproic acid anticonvulsant and toxic potencies in mice. Neuropharmacology. 1985;24:427–435
  81. Löscher W, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs IV. Protective indices. Epilepsy Res. 1991;9:1–10
  82. Löscher W, Rogawski MA. Epilepsy. In:  Lodge D,  Danysz W,  Parsons CG editor. Ionotropic Glutamate Receptors as Therapeutic Targets. Johnson City, TN: F.P. Graham Publishing Co.; 2002;p. 91–132
  83. Löscher W, Rundfeldt C, Honack D. Low doses of NMDA receptor antagonists synergistically increase the anticonvulsant effect of the AMPA receptor antagonist NBQX in the kindling model of epilepsy. Eur. J. Neurosci. 1993;5:1545–1550
  84. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. Acad. Sci. U.S.A. 2004;101:9861–9866
  85. Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA. Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol. Pharmacol. 2000;58:253–262
  86. Marescaux C, Vergnes M, Depaulis A. Genetic absence epilepsy in rats from Strasbourg—a review. J. Neural. Transm. Suppl. 1992;35:37–69
  87. McAuley JW, Moore JL, Reeves AL, Flyak J, Monaghan EP, Data J. A pilot study of the neurosteroid ganaxolone in catamenial epilepsy: clinical experience in two patients. Epilepsia. 2001;42(Suppl. 7):85
  88. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat. Neurosci. 2000;3:587–592
  89. McLean MJ, Schmutz M, Pozza M, Wamil A. The influence of rufinamide on sodium currents and action potential firing in rodent neurons. Epilepsia. 2005;46(Suppl. 8):296;(3.061)
  90. Monaghan EP, McAuley JW, Data JL. Ganaxolone: a novel positive allosteric modulator of the GABAA receptor complex for the treatment of epilepsy. Expert Opin. Investig. Drugs. 1999;8:1663–1671
  91. Nau H, Löscher W. Pharmacologic evaluation of various metabolites and analogs of valproic acid: teratogenic potencies in mice. Fundam. Appl. Toxicol. 1986;6:669–676
  92. Nehlig A, Rigoulot M-A, Boehrer A. A new drug, RWJ 333369 displays potent antiepileptic properties in genetic models of absence and audiogenic epilepsy. Epilepsia. 2005;46(Suppl. 8):215;(2.368)
  93. Nielsen EØ, Varming T, Mathiesen C, Jensen LH, Moller A, Gouliaev AH, et al. SPD 502: a water-soluble and in vivo long-lasting AMPA antagonist with neuroprotective activity. J. Pharmacol. Exp. Ther. 1999;289:1492–1501
  94. Nusser Z, Sieghart W, Somogyi P. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 1998;18:1693–1703
  95. Otto JF, Kimball MM, Wilcox KS. Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission. Mol. Pharmacol. 2002;61:921–927
  96. Parada A, Soares-da-Silva P. The novel anticonvulsant BIA 2-093 inhibits transmitter release during opening of voltage-gated sodium channels: a comparison with carbamazepine and oxcarbazepine. Neurochem. Int. 2002;40:435–440
  97. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16:695–714
  98. Petersen EN. DMCM: a potent convulsive benzodiazepine receptor ligand. Eur. J. Pharmacol. 1983;94:117–124
  99. Pisani F, Fazio A, Artesi C, Oteri G, Spina E, Tomson T, et al. Impairment of carbamazepine-10,11-epoxide elimination by valnoctamide, a valpromide isomer, in healthy subjects. Br. J. Clin. Pharmacol. 1992;34:85–87
  100. Pisani F, Haj-Yehia A, Fazio A, Artesi C, Oteri G, Perucca E, et al. Carbamazepine–valnoctamide interaction in epileptic patients: in vitro/in vivo correlation. Epilepsia. 1993;34:954–959
  101. Pitkänen A. Drug-mediated neuroprotection and antiepileptogenesis: animal data. Neurology. 2002;59(9 Suppl. 5):S27–S33
  102. Pitkänen A, Kharatishvili I, Narkilahti S, Lukasiuk K, Nissinen J. Administration of diazepam during status epilepticus reduces development and severity of epilepsy in rat. Epilepsy Res. 2005;63:27–42
  103. Pugliese AM, Passani MB, Pepeu G, Corradetti R. Felbamate decreases synaptic transmission in the CA1 region of rat hippocampal slices. J. Pharmacol. Exp. Ther. 1996;279:1100–1108
  104. Radatz M, Ehlers K, Yagen B, Bialer M, Nau H. Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid. Epilepsy Res. 1998;30:41–48
  105. Reddy DS, Castaneda DC, O’Malley BW, Rogawski MA. Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice. J. Pharmacol. Exp. Ther. 2004;310:230–239
  106. Reddy DS, Rogawski MA. Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J. Pharmacol. Exp. Ther. 2000;295:1241–1248
  107. Reddy DS, Rogawski MA. Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy. J. Pharmacol. Exp. Ther. 2000;294:909–915
  108. Reddy DS, Rogawski MA. Enhanced anticonvulsant activity of neuroactive steroids in a rat model of catamenial epilepsy. Epilepsia. 2001;42:337–344
  109. Reddy DS, Rogawski MA. Stress-induced deoxycorticosterone-derived neurosteroids modulate GABAA receptor function and seizure susceptibility. J. Neurosci. 2002;22:3795–3805
  110. Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-d-aspartate and γ-aminobutyric acidA receptors. Ann. Neurol. 1994;35:229–234
  111. Rigdon, G.C., Roeloffs, R., Wickenden, A.D., McNaughton-Smith, G., Jones, L., Harrison, W., Ghodadra, N., McNamara, J.O., 2005. In vivo profile of ICA-27243, a potent and selective KCNQ2/3 activator in rodent anticonvulsant models. Soc. Neurosci. Abst. Prog. No. 153.15.
  112. Rogawski MA. Mechanism-specific pathways for new antiepileptic drug discovery. In:  French J,  Leppik I,  Dichter MA editor. Advances in Neurology. vol. 76:Philadelphia: Lippincott-Raven Publishers; 1998;p. 11–27
  113. Rogawski MA. Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. Trends Pharmacol. Sci. 1993;14:325–331
  114. Rogawski MA. Epilepsy. In:  Pullan L,  Patel J editor. Neurotherapeutics: Emerging Strategies. Totowa, NJ: Humana Press; 1996;p. 193–273
  115. Rogawski MA. KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. Trends Neurosci. 2000;23:393–398
  116. Rogawski MA. Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res. 2006;68:22–28
  117. Rogawski MA, Donevan SD. AMPA receptors in epilepsy and as targets for antiepileptic drugs. Adv. Neurol. 1999;79:947–963
  118. Rogawski MA, Kurzman PS, Yamaguchi SI, Li H. Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse. Neuropharmacology. 2001;40:28–35
  119. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci. 2004;5:553–564
  120. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat. Med. 2004;10:685–692
  121. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol. Rev. 1990;42:223–286
  122. Rogawski MA, Reddy DS. Neurosteroids: endogenous modulators of seizure susceptibility. In:  Rho JM,  Sankar R,  Cavazos J editor. Epilepsy: Scientific Foundations of Clinical Practice. New York: Marcel Dekker; 2004;p. 319–355
  123. Rogawski, M.A., Taylor, C.P., 2006. Calcium channel α2-δ subunit, a new antiepileptic drug target. Epilepsy Res., in press.
  124. Rostock A, Tober C, Rundfeldt C, Bartsch R, Engel J, Polymeropoulos EE, et al. D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res. 1996;23:211–223
  125. Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, et al. Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature. 1999;401:796–800
  126. Rundfeldt C. The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. Eur. J. Pharmacol. 1997;336:243–249
  127. Rundfeldt C, Netzer R. Investigations into the mechanism of action of the new anticonvulsant retigabine. Interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels. Arzneimittelforschung. 2000;50:1063–1070
  128. Rundfeldt C, Netzer R. The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits. Neurosci. Lett. 2000;282:73–76
  129. Sachdeo R, Porter R, Biton V, Rosenfeld W, Alves W, Nohria V. Dose finding study of retigabine (a novel AED) in patients with epilepsy. Epilepsia. 2005;46(Suppl. 8):185;(2.280)
  130. Sarro G, Ferreri G, Gareri P, Russo E, De Sarro A, Gitto R, et al. Comparative anticonvulsant activity of some 2,3-benzodiazepine derivatives in rodents. Pharmacol. Biochem. Behav. 2003;74:595–602
  131. Schenzer A, Friedrich T, Pusch M, Saftig P, Jentsch TJ, Grotzinger J, et al. Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. J. Neurosci. 2005;25:5051–5060
  132. Schmidt D, Rogawski MA. New strategies for the identification of drugs to prevent the development or progression of epilepsy. Epilepsy Res. 2002;50:71–78
  133. Schmutz M, Allgeier H, Jeker A, Klebs K, McLean MJ, Mondadori C, et al. Anticonvulsant profile of CGP 33101 in animals. Epilepsia. 1993;34(2):122
  134. Schroeder BC, Kubisch C, Stein V, Jentsch TJ. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature. 1998;396:687–690
  135. Shen M, Béguin C, Golbraikh A, Stables JP, Kohn H, Tropsha A. Application of predictive QSAR models to database mining: identification and experimental validation of novel anticonvulsant compounds. J. Med. Chem. 2004;47:2356–2364
  136. Simeone TA, McClellan AM. Felbamate demonstrates subunit selective activity in recombinant GABA-A receptors. Epilepsia. 2000;41(Suppl. 7):36
  137. Sobol E, Bialer M, Yagen B. Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives. J. Med. Chem. 2004;47:4316–4326
  138. Sobol E, Yagen B, Winkler I, Britzi M, Gibson D, Bialer M. Pharmacokinetics and metabolism of a new potent antiepileptic drug 2,2,3,3-tetramethycyclopropanecarbonylurea, in rats. Drug Metab. Dispos. 2005;33:1538–1546
  139. Spiegelstein O, Yagen B, Levy RH, Finnell RH, Bennett GD, Roeder M, et al. Stereoselective pharmacokinetics and pharmacodynamics of propylisopropyl acetamide, a CNS-active chiral amide analog of valproic acid. Pharm. Res. 1999;16:1582–1588
  140. Stables, J.P., Bertram, E.H., White, H.S., Coulter, D.A., Dichter, M.A., Jacobs, M.P., Löscher, W., Lowenstein, D.H., Moshé, S.L., Noebels, J.L., Davis, M., 2002. Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland. Epilepsia 43, 1410–1420.
  141. Stefani A, Calabresi P, Pisani A, Mercuri NB, Siniscalchi A, Bernardi G. Felbamate inhibits dihydropyridine-sensitive calcium channels in central neurons. J. Pharmacol. Exp. Ther. 1996;277:121–127
  142. Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors. Proc. Natl. Acad. Sci. U.S.A. 2003;100:14439–14444
  143. Subramaniam S, Rho JM, Penix L, Donevan SD, Fielding RP, Rogawski MA. Felbamate block of the N-methyl-d-aspartate receptor. J. Pharmacol. Exp. Ther. 1995;273:878–886
  144. Taglialatela M, Ongini E, Brown AM, Di Renzo G, Annunziato L. Felbamate inhibits cloned voltage-dependent Na+ channels from human and rat brain. Eur. J. Pharmacol. 1996;316:373–377
  145. Takahashi M, Ni JW, Kawasaki-Yatsugi S, Toya T, Yatsugi SI, Shimizu-Sasamata M, et al. YM872, a novel selective α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, reduces brain damage after permanent focal cerebral ischemia in cats. J. Pharmacol. Exp. Ther. 1998;284:467–473
  146. Tatulian L, Brown DA. Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells. J. Physiol. 2003;549(Pt 1):57–63
  147. Tatulian L, Delmas P, Abogadie FC, Brown DA. Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J. Neurosci. 2001;21:5535–5545
  148. Thompson CD, Miller TA, Barthen MT, Dieckhaus CM, Sofia RD, Macdonald TL. The synthesis, in vitro reactivity, and evidence for formation in humans of 5-phenyl-1,3-oxazinane-2,4-dione, a metabolite of felbamate. Drug Metab. Dispos. 2000;28:434–439
  149. Tober C, Rostock A, Rundfeldt C, Bartsch R. D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures. Eur. J. Pharmacol. 1996;303:163–169
  150. Troughton, G.M., Kleckner, N.M., 2005. An Investigation of the subtype-selective antagonism of N-methyl-d-aspartate receptors by new antiepileptic agent, R-2-acetamido-N-benzyl-3-methoxypropionamide, Bates College Thesis Abst.
  151. Turski L, Huth A, Sheardown M, McDonald F, Neuhaus R, Schneider HH, et al. ZK200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc. Natl. Acad. Sci. U.S.A. 1998;95:10960–10965
  152. van Rijn CM, Willems-van Bree E. Synergy between retigabine and GABA in modulating the convulsant site of the GABAA receptor complex. Eur. J. Pharmacol. 2003;464:95–100
  153. Vickery RG, Amagasu SM, Chang R, Mai N, Kaufman E, Martin J, et al. Comparison of the pharmacological properties of rat NaV1.8 with rat NaV1.2a and human NaV1.5 voltage-gated sodium channel subtypes using a membrane potential sensitive dye and FLIPR. Receptors Channels. 2004;10:11–23
  154. Volosov A, Xiaodong S, Perucca E, Yagen B, Sintov A, Bialer M. Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects. Clin. Pharmacol. Ther. 1999;66:547–553
  155. Walters MR, Kaste M, Lees KR, Diener HC, Hommel M, De Keyser J, et al. The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study. Cerebrovasc. Dis. 2005;20:304–309
  156. Watanabe H, Nagata E, Kosakai A, Nakamura M, Yokoyama M, Tanaka K, et al. Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J. Neurochem. 2000;75:28–33
  157. White HS, Schmutz M, Pozza M, Wolf H, Stables J, Kupferberg H. The anticonvulsant profile and tolerability of rufinamide in mice and rats. Epilepsia. 2005;46(Suppl. 8):304–306(3.088)
  158. White HS, Wolf HH, Swinyard EA, Skeen GA, Sofia RD. A neuropharmacological evaluation of felbamate as a novel anticonvulsant. Epilepsia. 1992;33:564–572
  159. White HS, Woodhead JH, Wilcox KS, Stables JP, Kupferberg HJ, Wolf HH. General principles discovery and preclinical development of antiepileptic drugs. In:  Levy RH,  Mattson RH,  Meldrum BS,  Perucca E editor. Antiepileptic Drugs. Philadelphia: Lippincott-Raven; 2002;p. 36–48
  160. Whiting PJ. The GABAA receptor gene family: new opportunities for drug development. Curr. Opin. Drug Discov. Devel. 2003;6:648–657
  161. Wickenden, A.D., McNaughton-Smith, G., Roeloffs, R., London, B., Clark, S., Wilson, W.A., Rigdon, G.C., Wagoner, P.K., 2005. ICA-27243: A novel, potent, and selective KCNQ2/Q3 potassium channel activator. Soc. Neurosci. Abst. Prog. No. 153.13.
  162. Wickenden AD, Zou A, Wagoner PK, Jegla T. Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. Br. J. Pharmacol. 2001;132:381–384
  163. Winkler I, Blotnik S, Shimshoni J, Yagen B, Devor M, Bialer M. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain. Br. J. Pharmacol. 2005;146:198–208
  164. Wohlfarth KM, Bianchi MT, Macdonald RL. Enhanced neurosteroid potentiation of ternary GABAA receptors containing the δ subunit. J. Neurosci. 2002;22:1541–1549
  165. Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H. The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol. Pharmacol. 2005;67:1009–1017
  166. Yamaguchi S, Donevan SD, Rogawski MA. Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBOX in maximal electroshock and chemoconvulsant seizure models. Epilepsy Res. 1993;15:179–184

PII: S0920-1211(06)00063-5

doi: 10.1016/j.eplepsyres.2006.02.004

Epilepsy Research
Volume 69, Issue 3 , Pages 273-294 , June 2006

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