Neuronal sprouting has recently been reported to be a phenotype of neurons treated with (R)-lacosamide. Although a number of unique pathways involving multiple
proteins may mediate this process, some proteins identified in our proteomic search have been associated with this phenomenon. NSF, the hexameric ATPase involved in disassembly of the SNARE complex, was identified specifically with the (R) entantiomer during the proteomic screen and the IC50 calculated to be 340 µM using the homologous
competition assay. This was the lowest ICd of all three proteins tested. Expression of a
dominant negative (ATPase inactive) mutant in drosophila results in outgrowth at the neuromuscular synapse during development.227 If the ATPase activity of NSF contributes to synpase sprouting, then potentially (R)-lacosamide may affect NSF activity. A standard ATPase assay using recombinant protein in the presence or absence of (R) and (S)-lacosamide would evaluate whether this hypothesis warrants further investigation.
5.6Metabolic profiling of (R)-lacosamide treated mice
The majority of our efforts have relied solely on the results of a proteomic screen to identify potential protein targets that interact with (R)-lacosamide coupled with in vitro
methods to measure labeling and binding affinity. Alternative methods that provide greater insight into the biochemical changes elicited by (R)-lacosamide would help distinguish between physiologically relevant proteins identified during our screen with those that should be considered background. As mentioned in chapter 2, advances in mass spectrometry now allow for simultaneous detection of hundreds of cellular metabolites from tissues to discern biochemical changes between samples. This methodology has been successfully applied for the identification of the protein targets of several drug candidates.141
A similar approach could be taken with (R)-lacosamide by profiling the four sets of mouse brain tissue used to generate the mRNA-display libraries [normal (sham stimulated), (R)-lacosamide treated (20 mg/kg), 6 Hz stimulated (32 mA 3 sec), and 6 Hz stimulated (R)-lacosamide treated]. The results would generate unique metabolic profiles for each tissue treatment that could readily be mapped to biochemical pathways in the cell. Changes in metabolites upon administration of (R)-lacosamide could then be integrated with the results of our proteomic screen, providing a better understanding of which biochemical pathways to pursue.
Bibliography
(1) World Health Organization Atlas Epilepsy Care in the World 2005; World Health Organization, 2005.
(2) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981, 22, 489-501.
(3) Squire, L. R. Fundamental neuroscience; Academic Press, 2008.
(4) Allen, N. J.; Barres, B. A. Neuroscience: Glia - more than just brain glue. Nature 2009,
457, 675-677.
(5) Collingridge, G. L.; Olsen, R. W.; Peters, J.; Spedding, M. A nomenclature for ligand- gated ion channels. Neuropharmacology 2009, 56, 2-5.
(6) Miller, P. S.; Smart, T. G. Binding, activation and modulation of Cys-loop receptors.
Trends Pharmacol Sci 2010.
(7) Shorvon, S. D. (. D. ). Handbook of epilepsy treatment : forms, causes and therapy in children and adults; 2nd ed.; Blackwell Pub.,: Malden, Mass., 2005.
(8) Fisher, J. L. A mutation in the GABAA receptor alpha 1 subunit linked to human epilepsy affects channel gating properties. Neuropharmacology 2004, 46, 629-637.
(9) Baulac, S.; Huberfeld, G.; Gourfinkel-An, I.; Mitropoulou, G.; Beranger, A.; Prud'homme, J. F.; Baulac, M.; Brice, A.; Bruzzone, R.; LeGuern, E. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2- subunit gene. Nat. Genet 2001, 28, 46-48.
(10) Wallace, R. H.; Marini, C.; Petrou, S.; Harkin, L. A.; Bowser, D. N.; Panchal, R. G.; Williams, D. A.; Sutherland, G. R.; Mulley, J. C.; Scheffer, I. E.; Berkovic, S. F. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.
Nat. Genet 2001, 28, 49-52.
(11) Harkin, L. A.; Bowser, D. N.; Dibbens, L. M.; Singh, R.; Phillips, F.; Wallace, R. H.; Richards, M. C.; Williams, D. A.; Mulley, J. C.; Berkovic, S. F.; Scheffer, I. E.; Petrou, S. Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet 2002, 70, 530-536.
(12) Bianchi, M. T.; Song, L.; Zhang, H.; Macdonald, R. L. Two different mechanisms of disinhibition produced by GABAA receptor mutations linked to epilepsy in humans. J. Neurosci 2002, 22, 5321-5327.
G. R.; Scheffer, I. E.; Berkovic, S. F. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet 1995, 11, 201-203.
(14) Leniger, T.; Kananura, C.; Hufnagel, A.; Bertrand, S.; Bertrand, D.; Steinlein, O. K. A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy. Epilepsia
2003, 44, 981-985.
(15) Hirose, S.; Iwata, H.; Akiyoshi, H.; Kobayashi, K.; Ito, M.; Wada, K.; Kaneko, S.; Mitsudome, A. A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology 1999, 53, 1749-1753.
(16) Chen, Y.; Wu, L.; Fang, Y.; He, Z.; Peng, B.; Shen, Y.; Xu, Q. A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy. Epilepsy Res 2009, 83, 152-156.
(17) Weiland, S.; Witzemann, V.; Villarroel, A.; Propping, P.; Steinlein, O. An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics. FEBS Lett 1996, 398, 91-96. (18) Steinlein, O. K.; Magnusson, A.; Stoodt, J.; Bertrand, S.; Weiland, S.; Berkovic, S. F.;
Nakken, K. O.; Propping, P.; Bertrand, D. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum. Mol. Genet
1997, 6, 943-947.
(19) McLellan, A.; Phillips, H. A.; Rittey, C.; Kirkpatrick, M.; Mulley, J. C.; Goudie, D.; Stephenson, J. B. P.; Tolmie, J.; Scheffer, I. E.; Berkovic, S. F.; Zuberi, S. M. Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia 2003, 44, 613-617.
(20) De Fusco, M.; Becchetti, A.; Patrignani, A.; Annesi, G.; Gambardella, A.; Quattrone, A.; Ballabio, A.; Wanke, E.; Casari, G. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat. Genet 2000, 26, 275-276.
(21) Figl, A.; Viseshakul, N.; Shafaee, N.; Forsayeth, J.; Cohen, B. N. Two mutations linked to nocturnal frontal lobe epilepsy cause use-dependent potentiation of the nicotinic ACh response. J. Physiol. (Lond.) 1998, 513 ( Pt 3), 655-670.
(22) Phillips, H. A.; Marini, C.; Scheffer, I. E.; Sutherland, G. R.; Mulley, J. C.; Berkovic, S. F. A de novo mutation in sporadic nocturnal frontal lobe epilepsy. Ann. Neurol 2000, 48, 264-267.
(23) Steinlein, O. K.; Bertrand, D. Nicotinic receptor channelopathies and epilepsy. Pflugers Arch 2009.
(24) Rogawski, M. A. KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. Trends Neurosci 2000, 23, 393-398.
(25) Singh, N. A.; Charlier, C.; Stauffer, D.; DuPont, B. R.; Leach, R. J.; Melis, R.; Ronen, G. M.; Bjerre, I.; Quattlebaum, T.; Murphy, J. V.; McHarg, M. L.; Gagnon, D.; Rosales, T. O.; Peiffer, A.; Anderson, V. E.; Leppert, M. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat. Genet 1998, 18, 25-29.
(26) Biervert, C.; Schroeder, B. C.; Kubisch, C.; Berkovic, S. F.; Propping, P.; Jentsch, T. J.; Steinlein, O. K. A potassium channel mutation in neonatal human epilepsy. Science 1998,
279, 403-406.
(27) Watanabe, H.; Nagata, E.; Kosakai, A.; Nakamura, M.; Yokoyama, M.; Tanaka, K.; Sasai, H. Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J. Neurochem 2000, 75, 28-33.
(28) Heilstedt, H. A.; Burgess, D. L.; Anderson, A. E.; Chedrawi, A.; Tharp, B.; Lee, O.; Kashork, C. D.; Starkey, D. E.; Wu, Y. Q.; Noebels, J. L.; Shaffer, L. G.; Shapira, S. K. Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome. Epilepsia 2001, 42, 1103-1111.
(29) Zuberi, S. M.; Eunson, L. H.; Spauschus, A.; De Silva, R.; Tolmie, J.; Wood, N. W.; McWilliam, R. C.; Stephenson, J. B.; Stephenson, J. P.; Kullmann, D. M.; Hanna, M. G. A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 1999, 122 ( Pt 5), 817-825.
(30) Eunson, L. H.; Rea, R.; Zuberi, S. M.; Youroukos, S.; Panayiotopoulos, C. P.; Liguori, R.; Avoni, P.; McWilliam, R. C.; Stephenson, J. B.; Hanna, M. G.; Kullmann, D. M.; Spauschus, A. Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Ann. Neurol 2000, 48, 647-656. (31) Mulley, J. C.; Scheffer, I. E.; Petrou, S.; Dibbens, L. M.; Berkovic, S. F.; Harkin, L. A.
SCN1A mutations and epilepsy. Hum. Mutat 2005, 25, 535-542.
(32) Lulic, D.; Ahmadian, A.; Baaj, A. A.; Benbadis, S. R.; Vale, F. L. Vagus nerve stimulation. Neurosurg Focus 2009, 27, E5.
(33) Uthman, B. M.; Reichl, A. M.; Dean, J. C.; Eisenschenk, S.; Gilmore, R.; Reid, S.; Roper, S. N.; Wilder, B. J. Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. Neurology 2004, 63, 1124-1126.
(34) Groves, D. A.; Brown, V. J. Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev 2005, 29, 493-500.
(35) Epilepsy Foundation-Surgery. Treatment Options: Surgery.
(36) Nylen, K.; Likhodii, S.; Burnham, W. M. The ketogenic diet: proposed mechanisms of action. Neurotherapeutics 2009, 6, 402-405.
(37) Beniczky, S.; Jose Miranda, M.; Alving, J.; Heber Povlsen, J.; Wolf, P. Effectiveness of the ketogenic diet in a broad range of seizure types and EEG features for severe childhood epilepsies. Acta Neurol. Scand 2010, 121, 58-62.
(38) Bough, K. Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. Epilepsia 2008, 49 Suppl 8, 91-93.
(39) Bough, K. J.; Rho, J. M. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia
2007, 48, 43-58.
(40) Weinshenker, D.; Szot, P. The role of catecholamines in seizure susceptibility: new results using genetically engineered mice. Pharmacol. Ther 2002, 94, 213-233.
(41) Yan, Q. S.; Jobe, P. C.; Dailey, J. W. Noradrenergic mechanisms for the anticonvulsant effects of desipramine and yohimbine in genetically epilepsy-prone rats: studies with microdialysis. Brain Res 1993, 610, 24-31.
(42) Epilepsy: A Comprehensive Textbook; 2nd ed.; Wolters Kluwer Health/Lippincott Williams & Wilkins: Philadelphia, 2008.
(43) Ben-Menachem, E. Eslicarbazepine acetate: a well-kept secret? Epilepsy Curr 2010, 10, 7-8.
(44) Pearce, R. E.; Lu, W.; Wang, Y.; Uetrecht, J. P.; Correia, M. A.; Leeder, J. S. Pathways of carbamazepine bioactivation in vitro. III. The role of human cytochrome P450 enzymes in the formation of 2,3-dihydroxycarbamazepine. Drug Metab. Dispos 2008, 36, 1637-1649.
(45) Bialer, M.; Johannessen, S. I.; Levy, R. H.; Perucca, E.; Tomson, T.; White, H. S. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res 2009, 83, 1-43.
(46) Kuo, C. C. A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol. Pharmacol 1998, 54, 712-721.
(47) Mintzer, S.; Mattson, R. T. Should enzyme-inducing antiepileptic drugs be considered first-line agents? Epilepsia 2009, 50 Suppl 8, 42-50.
(48) Gidal, B. E.; French, J. A.; Grossman, P.; Le Teuff, G. Assessment of potential drug interactions in patients with epilepsy: impact of age and sex. Neurology 2009, 72, 419- 425.
(49) Taverna, S.; Sancini, G.; Mantegazza, M.; Franceschetti, S.; Avanzini, G. Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate. J. Pharmacol. Exp. Ther 1999, 288, 960-968.
Neurosci 2003, 23, 7069-7074.
(51) White, H. S.; Brown, S. D.; Woodhead, J. H.; Skeen, G. A.; Wolf, H. H. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res 1997, 28, 167-179.
(52) Braga, M. F. M.; Aroniadou-Anderjaska, V.; Li, H.; Rogawski, M. A. Topiramate reduces excitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons. J. Pharmacol. Exp. Ther 2009, 330, 558-566.
(53) Kaminski, R. M.; Banerjee, M.; Rogawski, M. A. Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist. Neuropharmacology 2004,
46, 1097-1104.
(54) Angehagen, M.; Ben-Menachem, E.; Shank, R.; Rönnbäck, L.; Hansson, E. Topiramate modulation of kainate-induced calcium currents is inversely related to channel phosphorylation level. J. Neurochem 2004, 88, 320-325.
(55) Kwan, P.; Brodie, M. J. Phenobarbital for the treatment of epilepsy in the 21st century: a critical review. Epilepsia 2004, 45, 1141-1149.
(56) MacDonald, R. L.; Rogers, C. J.; Twyman, R. E. Barbiturate regulation of kinetic properties of the GABAA receptor channel of mouse spinal neurones in culture. J. Physiol. (Lond.) 1989, 417, 483-500.
(57) Twyman, R. E.; Rogers, C. J.; Macdonald, R. L. Differential regulation of gamma- aminobutyric acid receptor channels by diazepam and phenobarbital. Ann. Neurol 1989,
25, 213-220.
(58) Rho, J. M.; Donevan, S. D.; Rogawski, M. A. Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J. Physiol. (Lond.) 1996, 497 ( Pt 2), 509-522.
(59) van der Laan, J. W.; de Boer, T.; Bruinvels, J. Di-n-propylacetate and GABA degradation. Preferential inhibition of succinic semialdehyde dehydrogenase and indirect inhibition of GABA-transaminase. J. Neurochem 1979, 32, 1769-1780.
(60) Johannessen, C. U. Mechanisms of action of valproate: a commentatory. Neurochem. Int
2000, 37, 103-110.
(61) Toth, M. The epsilon theory: a novel synthesis of the underlying molecular and electrophysiological mechanisms of primary generalized epilepsy and the possible mechanism of action of valproate. Med. Hypotheses 2005, 64, 267-272.
(62) Bazinet, R. P.; Weis, M. T.; Rapoport, S. I.; Rosenberger, T. A. Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-
(Berl.) 2006, 184, 122-129.
(63) Rosenberg, G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell. Mol. Life Sci 2007, 64, 2090-2103.
(64) Hendrich, J.; Van Minh, A. T.; Heblich, F.; Nieto-Rostro, M.; Watschinger, K.; Striessnig, J.; Wratten, J.; Davies, A.; Dolphin, A. C. Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proc. Natl. Acad. Sci. U.S.A 2008, 105, 3628-3633.
(65) Abdul-Ghani, A. S.; Coutinho-Netto, J.; Bradford, H. F. The action of gamma-vinyl- GABA and gamma-acetylenic-GABA on the resting and stimulated release of GABA in vivo. Brain Res 1980, 191, 471-481.
(66) Petroff, O. A.; Behar, K. L.; Mattson, R. H.; Rothman, D. L. Human brain gamma- aminobutyric acid levels and seizure control following initiation of vigabatrin therapy. J. Neurochem 1996, 67, 2399-2404.
(67) Nakamura, F.; Suzuki, S.; Nishimura, S.; Yagi, K.; Seino, M. Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture.
Epilepsia 1996, 37, 728-735.
(68) Coulter, D. A.; Huguenard, J. R.; Prince, D. A. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann. Neurol 1989, 25, 582-593.
(69) Kito, M.; Maehara, M.; Watanabe, K. Mechanisms of T-type calcium channel blockade by zonisamide. Seizure 1996, 5, 115-119.
(70) Suzuki, S.; Kawakami, K.; Nishimura, S.; Watanabe, Y.; Yagi, K.; Seino, M.; Miyamoto, K. Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex.
Epilepsy Res 1992, 12, 21-27.
(71) Schauf, C. L. Zonisamide enhances slow sodium inactivation in Myxicola. Brain Res
1987, 413, 185-188.
(72) Mimaki, T.; Suzuki, Y.; Tagawa, T.; Karasawa, T.; Yabuuchi, H. Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain. Med J Osaka Univ
1990, 39, 13-17.
(73) Macdonald, R. L.; Greenfield, L. J. Mechanisms of action of new antiepileptic drugs.
Curr. Opin. Neurol 1997, 10, 121-128.
(74) Sander, J. W.; Patsalos, P. N. An assessment of serum and red blood cell folate concentrations in patients with epilepsy on lamotrigine therapy. Epilepsy Res 1992, 13, 89-92.
neuronal voltage-activated sodium channels. Epilepsy Res 1992, 13, 107-112.
(76) Rekling, J. C.; Jahnsen, H.; Mosfeldt Laursen, A. The effect of two lipophilic gamma- aminobutyric acid uptake blockers in CA1 of the rat hippocampal slice. Br. J. Pharmacol
1990, 99, 103-106.
(77) Nielsen, E. B.; Suzdak, P. D.; Andersen, K. E.; Knutsen, L. J.; Sonnewald, U.; Braestrup, C. Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor. Eur. J. Pharmacol 1991, 196, 257-266.
(78) Pellock, J. M. Felbamate in epilepsy therapy: evaluating the risks. Drug Saf 1999, 21, 225-239.
(79) Harty, T. P.; Rogawski, M. A. Felbamate block of recombinant N-methyl-D-aspartate receptors: selectivity for the NR2B subunit. Epilepsy Res 2000, 39, 47-55.
(80) Taglialatela, M.; Ongini, E.; Brown, A. M.; Di Renzo, G.; Annunziato, L. Felbamate inhibits cloned voltage-dependent Na+ channels from human and rat brain. Eur. J. Pharmacol 1996, 316, 373-377.
(81) Kume, A.; Greenfield, L. J.; Macdonald, R. L.; Albin, R. L. Felbamate inhibits [3H]t- butylbicycloorthobenzoate (TBOB) binding and enhances Cl- current at the gamma- aminobutyric AcidA (GABAA) receptor. J. Pharmacol. Exp. Ther 1996, 277, 1784-1792. (82) Rho, J. M.; Donevan, S. D.; Rogawski, M. A. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-D-aspartate and gamma-aminobutyric acidA receptors. Ann. Neurol 1994, 35, 229-234.
(83) Kuo, C.; Lin, B.; Chang, H.; Hsieh, C. 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.
(84) Lynch, B. A.; Lambeng, N.; Nocka, K.; Kensel-Hammes, P.; Bajjalieh, S. M.; Matagne, A.; Fuks, B. 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) Janz, R.; Goda, Y.; Geppert, M.; Missler, M.; Südhof, T. C. SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron 1999, 24, 1003-1016. (86) Matagne, A.; Margineanu, D.; Kenda, B.; Michel, P.; Klitgaard, H. Anti-convulsive and
anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. Br. J. Pharmacol 2008, 154, 1662-1671.
(87) Zona, C.; Pieri, M.; Carunchio, I.; Curcio, L.; Klitgaard, H.; Margineanu, D. G. Brivaracetam (ucb 34714) inhibits Na(+) current in rat cortical neurons in culture.
The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models.
Epilepsia 2008, 49, 1213-1220.
(89) McLean, M. J.; Schmutz, M. The Influence of Rufinamide on Sodium Currents and Action Potential Firing in Rodent Neurons. Epilepsia 2005, 46, 296.
(90) UCB :: UCB's Vimpat® approved by U.S. FDA as adjunctive therapy for partial onset seizures in adults.
(91) Clinical Trials.gov Search of: Lacosamide neuropathic pain - List Results - ClinicalTrials.gov.
(92) Conley, J. D.; Kohn, H. Functionalized DL-amino acid derivatives. Potent new agents for the treatment of epilepsy. J. Med. Chem 1987, 30, 567-574.
(93) Shorvon, S. D.; Fish, D.; Dodson, W. E. The treatment of epilepsy; Wiley-Blackwell, 2004.
(94) Choi, D.; Stables, J. P.; Kohn, H. The anticonvulsant activities of functionalized N- benzyl 2-acetamidoacetamides. The importance of the 2-acetamido substituent. Bioorg. Med. Chem 1996, 4, 2105-2114.
(95) Kohn, H.; Sawhney, K. N.; LeGall, P.; Conley, J. D.; Robertson, D. W.; Leander, J. D. Preparation and anticonvulsant activity of a series of functionalized alpha-aromatic and alpha-heteroaromatic amino acids. J. Med. Chem 1990, 33, 919-926.
(96) Kohn, H.; Sawhney, K. N.; Bardel, P.; Robertson, D. W.; Leander, J. D. Synthesis and anticonvulsant activities of alpha-heterocyclic alpha-acetamido-N-benzylacetamide derivatives. J. Med. Chem 1993, 36, 3350-3360.
(97) Bardel, P.; Bolanos, A.; Kohn, H. Synthesis and anticonvulsant activities of alpha- acetamido-N-benzylacetamide derivatives containing an electron-deficient alpha- heteroaromatic substituent. J. Med. Chem 1994, 37, 4567-4571.
(98) Choi, D.; Stables, J. P.; Kohn, H. Synthesis and anticonvulsant activities of N-Benzyl-2- acetamidopropionamide derivatives. J. Med. Chem 1996, 39, 1907-1916.
(99) LeTiran, A.; Stables, J. P.; Kohn, H. Design and evaluation of affinity labels of functionalized amino acid anticonvulsants. J. Med. Chem 2002, 45, 4762-4773.
(100) Stöhr, T.; Kupferberg, H. J.; Stables, J. P.; Choi, D.; Harris, R. H.; Kohn, H.; Walton, N.; White, H. S. Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy. Epilepsy Res 2007, 74, 147-154.
(101) Bialer, M.; White, H. S. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 2010, 9, 68-82.
(103) Schwarz Pharma Lacosamide Has a Novel Dual Mode of Action 2006.
(104) Sheets, P. L.; Heers, C.; Stoehr, T.; Cummins, T. R. Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl- 3-methoxypropanamide], lidocaine, and carbamazepine. J. Pharmacol. Exp. Ther 2008,