三唑并喹啉酮类化合物的合成及其抗癫痫活性的研究
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摘要
为了寻找具有更好抗惊厥活性及低神经毒性的化合物,本篇论文以6-羟基-3,4-二氢-2(1H)-喹啉酮为起始原料合成了12个2-取代7-庚氧基-4,5-二氢-[1,2,4]三氮唑[4,3-a]喹啉-1-酮衍生物和4个2-取代7-苄氧基-4,5-二氢-[1,2,4]三氮唑[4,3-a]喹啉-1-酮衍生物,对目标化合物,采用小鼠最大电惊厥实验(MES),皮下戊四唑实验(sc-PTZ)测定了其抗惊厥活性,采用旋转法测定了神经毒性。药理实验结果显示目标化合物表现出了较强的抗惊厥活性,其中化合物4b对MES实验的半数有效量为8.18 mg/kg,保护指数为39,明显高于多种上市药品,如:苯妥英纳,卡马西平,苯巴比妥和丙戊酸纳(保护指数的范围1.6-8.1);活性也高于先导化合物3。该结论证明喹啉并三氮唑化合物具有被开发为新型癫痫治疗药的优良品质。
To Find compounds with better anticonvulsant activity and lower neurotoxicity,twelve 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]-triazolo[4,3-a]quinolin-1(2H)-ones and four 2-substituted-7-benzyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2H)-ones derivatives were synthesized using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as a starting material,and their anticonvulsant activities were evaluated by the maximal electroshock test(MES) and the subcutaneous pentylenetetrazole test(sc-PTZ) and their neurotoxicities were measured by the rotarod neurotoxicity test(Tox).The results showed that 2-propionyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2 H)-one(4b) was the most potent with ED_(50) values of 8.18 mg/kg and the protective index(PI = TD_(50)/ED_(50)) values of 39 in the MES.The PI values of 4b was better than that of the marketed drugs phenytoin,carbamazepin, phenobarbital and valproate which have PI values in the range of 1.6-8.1 in the MES test.It also better than the lead compound 3.It was found that [1,2,4]triazole[4,3-a]quinolin-1-ones possess the potent of being explored to be a new anticonvulsant agent.
To Find compounds with better anticonvulsant activity and lower neurotoxicity,twelve 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]-triazolo[4,3-a]quinolin-1(2H)-ones and four 2-substituted-7-benzyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2H)-ones derivatives were synthesized using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as a starting material,and their anticonvulsant activities were evaluated by the maximal electroshock test(MES) and the subcutaneous pentylenetetrazole test(sc-PTZ) and their neurotoxicities were measured by the rotarod neurotoxicity test(Tox).The results showed that 2-propionyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2 H)-one(4b) was the most potent with ED_(50) values of 8.18 mg/kg and the protective index(PI = TD_(50)/ED_(50)) values of 39 in the MES.The PI values of 4b was better than that of the marketed drugs phenytoin,carbamazepin, phenobarbital and valproate which have PI values in the range of 1.6-8.1 in the MES test.It also better than the lead compound 3.It was found that [1,2,4]triazole[4,3-a]quinolin-1-ones possess the potent of being explored to be a new anticonvulsant agent.
引文
[1]Loscher W.New visions in the pharmacology of anticonvulsion.Eur J Pharmacol,1998,342,1-13
[2]张庆松,抗癫痫药物的应用原则和治疗进展.医学导报,2000,19(15):421-3
[2]Leppik IE.Antiepileptic drugs in development:prospects for the near future.Epilepsia,1994,35,S4,29-40
[3]Nishi T,Kimura Y,Nakagawa K.Research and development of cilostazol:an ntiplatelet agent.Yakugaku Zasshi,2000,120,1247-60
[4]Perucca E.The new generation of antiepileptic drugs:advantages and disadvantages.Br J Clin Pharmacol,1996,42(5),531-43
[5]Joseph B,Darro F,Behard A,Lesur B,Collignon F,Decaestecker C,Frydman A,Guillaumet G,Kiss R.3-Aryl-2-quinolone derivatives:synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a newtherapeutical target connected with cell migration.J Med Chem,2002,45:2543-55
[6]Xiao Z,Waters NC,Woodard CL,Li Z,Li PK.Design and synthesis of Pfmrkinhibitors as potential anti-malarial agents.Bioorg Med Chem Lett,2001,11:2875-8
[7]Nishi T,Kimura Y,Nakagawa K.Research and development of cilostazol:an antiplatelet agent.Yakugaku Zasshi,2000,120:1247-60.
[8]Quan ZS.,Wang JM.,Lee WY.,Kwak KC.,Kang HC.,Chai KY.Synthesis of 6-alkyloxyl-3,4- dihydro-2(1H)-quinoliones and their Anticonvulsant Activities.Bull Kor Chem Soc,2005,26,1757-60
[9]Al-Soud YA,Al-Dweri MN,Al-Masoudi NA.Farmaco,2004,59:775-83.
[10]Labanauskas L,Udrenaite E,Gaidelis P,Brukstus A.Farmaco,2004,59:255-9
[11]Abak K,Sezer O,Akar A,Anac O.Eur J Med Chem,2003,38:215-8
[12]Gulerman NN,Dogan HN,Rollas S,Johansson C,Celik C Farmaco,2001,56:953-8
[13]Collin X,Sauleau A,Coulon J,Bioorg Med Chem Lett,2003,13:2601-5
[14]Cwiklicki A,Rehse K,Arch.Pharm(Weinheim),2004,337:156-63
[15]Cunha AC,Figueiredo JM,Tributino JL,Miranda AL,Castro HC,Zingali RB,Fraga CA,Souza MC,Ferreira VF,Barreiro EJ,Bioorg Med Chem,2003,11:2051-9
[16]Lazrek HB,Taourirte M,Oulih T,Barascut JL,Imbach JL,Pannecouque C,Witrouw M,De Clercq E.Nucleosides Nucleotides Nucleic Acids,2001,20:1949-60
[17]Kadaba PK.Curr Med Chem,2003.10:2081-108
[18]Kdaba PK,Stevenson PJ,P-Nnane I,Damani LA.Bioorg Med Chem,1996,4:65-78
[19]Kane JM,Baron BM,Dudley MW,Sorensen SM,Staeger MA,Miller FP.J Med Chem,1990,33:2772-7
[20]Cui LJ.,XieZF.,Piao HR.,Li G,Chai KY.,Quan ZS.Synthesis and anticonvulsant activity of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline.Biol Pharm Bull,2005,28,1216-20
[21]Xie ZF.,Chai KY.,Piao HR.,Kwak KC.,Quan ZS.Synthesis and anticonvulsant activity of 7-alkoxyl-4,5-dihydro-[1,2,4]triazole[4,3-a]quinolines.Bioorg Med Chem lett,2005,15,4803-5
[22]Jin HG,Sun XY,Chai XY,Piao HR,Quan ZS.Bioorg Med Chem,2006,Oct 15;14(20):6868-73
[23]Xian YS,Yun ZJ,Fu NL,Gao L,Kyu YC,and Zhe SQ.Arch Pharm Res,2006,29(12)1080-5
[24]Krall RJ.,Penry JK.,White BG.,Kupferberg HJ.Antiepileptic drug development:Ⅱ.Anticonvulsant drug screening.Epilepsia,1978,19,409-28
[25]Poter RJ.,Cereghino JJ.,Gladding GD.,Hessie BJ.,Kupferberg HJ.,Scoville B.Antiepileptic drug development program.Clev Clin J Med,1984,51,293-305
[1]Rodriguez-River L.Considerations on the concept of epilepsy.Rev Neurol,1999,28:1159-61
[2]Kumar R.Classification and the need to classify epilepsy.Indian J Pediatr,2000,67:S4-11
[3]Bell GS,Sander JW.The epidemiology of epilepsy:The size of problem.Seizure,2002,1:306-14
[4]Oun A,Haldre S,Magi M.Prevalence of adult epilepsy in Estonial.Epilepsy Res,2003;8:171-81
[5]Ducan JS.The promise of new antiepileptic drugs.Br J Clin Pharmacol,2002:53:123-31
[6]Selak I.Pregabalin(Pfizer).Curt Opin Investig Drugs,2001,2:828-34
[7]Taylor CP,Vartanian MG,Yuen PW.Potent and stereospeciflc anticonsul-tant activity of 3-isobutyl GABA relates to in vitrobinding at a novel site labeled by tritated gabapentin.Epilepsy Res,1993,14:11-5
[8]Whitworth TL,Quick MW.Upregulation of grama-aminobutyric acid transporter expession:Role of alkylated aminobutyric acid derivatives.Biochem Soc Trans,2001,29:736-41
[9]Hurley RW,Chatterjea D,Rose,Feng M.Gabapentin and Pregabalin can interact synergistically with naproxen to produce antihyperalgesial.Anesehesiology,2002,97:1263-76
[10]Huppertz HJ,Feuerstein TJ,Schulze-Bonhage A.Myoclonus in epilepsy patients with anticonvulsive add-on therapy with pregabalinl.Epilepsia,2001,42:790-792
[11]Cater RB,Wood PL,Wieland S.Characterization of anticonvulsant prop-erties of ganaxolone(CCd 1042;3a-hydroxy-313-metyhl-5a-pregnan-20-one),a selective,high-affinity.steroid modulator Of the aminobutyri acid receptor.J Pharmacol Exp Ther,1997,280:1285-95
[12]Gasior M,Cater RB,Goldberg SR.Anticonvulsant and behavioral effects of nueroactive steroids alone and in conianction with diazepaml.Pharmacol Exp Ther,1997,282:543-53
[13]Gasior M,Ungard JT,Beekman M.Acute and chronic efects of the synthetic neuroactive steroid,ganaxolone.against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice:Comparison with diazepam and volproate,Neurophar-maeology,2000,39:1184-96
[14]Reddy DS.Newer GABAergie agents for pharmaeyotherapy of infantilespasms. Drugs Today,2002,38:657-75
[15]Kaminski RM.Van Rijn CM.Turski WA.AMPA and GABAa receptor antagonist and their interaction an rats with a genetic form of absence epilepsy.Eur J Pharmaeol,2001,430:251-4
[16]Soudijn W.Wijingaarden I.The GABA transporter and its inhibitors.Curr Med Chem,2000,15:339-50
[17]Posson M,Huguet F,Sa vattier A.A new type of anticonvulsant,stiri-pentol.Pharmacological profile and neurochemieal study.Arzneim Forsch Drug Res,1984,34:199-204
[18]Karle J.Antisense studies of brain GABAa receptors.Dan Med Bull,2002,49:130-44
[19]Stavem K.Loge JH.Kassa S.Health status of people with epilepsy compared with a general reference population.Epilepsia,2000,41:85-90
[20]Gill R,AIanine A,Bourson A.Pharmacological eharacterization of Ro 63-1908(1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-meth-yl-benzyl)-piperidin-4-o 1) a novel subtype-selective N-methyl-D-aspartate antagonist.J Pharmacol Exp rher,2002,302:940-8
[21]Promk M,Castellino FJ.Structure-function relationships of the NMDA receptor antagonist conantokin peptides.Curt Drug Targets,2001,2:313-22
[22]Donevan SD,McCabe RT.Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors.Mol Pharmaeol,2000,58:614-23
[23]Jansen M,Potsehka H,Brandt C.Hydantoin substituted 4,6-dichloroindole-2-carboxylic acids as legends with high affinity for glyeine binding site of the NMDA receptor.J Med Chem,2003,46:64-73
[24]Srinivasan J.Richens A.Davies JA.The efect of losigamone(AO-33)on electrical activity and excitatory amino acid release in mouse cortical slices.Br J Pharmacol,1997,11:1490-4
[25]Gebhardt C,Breustedt JM,Noldner M.The antiepileptic drug losigamone decreases the persistent Na~+ current in rat hippocampal neurons.Brain Res,2001.920:27-31
[26]Bauer J,Schwalen S.Topiramate(TopamaxTM) Pharmacological characteristics and current use in epilepsy treatment.Nervenarzt,2000,71:495-501
[27]Tortorella A,Halonen T,Sanhibzada N.A crucial role of α-amino-3-hydroxy -5-methyl-isoxazole-4-propionic acid subtype of Glutamaterec--eptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures.J Pharmacol Exp Ther.,1997,280:1401-5
[28]Aubelson YP.Compititive AMPA an tagonism:A novel mechanism for anti-epileptic drugs.Drugs Fut,2001,26:463-71
[29]Borowicz KK.Kleinrok Z.Czucawar SJ.The AMPA/kainite receptor antagonist,LY300164,increases the anticonvulsant effects of diazepam.Arch Pharmacol,2000,361:629-635
[30]Lodge D,Bond A;o'Naill MJ.Stereoselective efects of 2.3-benzodiazepines invivo:Electrophysiology and neuroprotection studies.Nettropharmacology,1996.35:1681-8
[31]Ohno K,Tsutsumi R,Matsumoto N.Functional characterization of YM928,a novel non-competitive α-amino-3 hydroxy-5-methyl-4-isoxazoleprop ionic acid(AMPA)receptor antagonist.J Pharmacol Exp Ther,2003:303:66-72
[32]WeiserT,BrennerM,Palluk R.BⅡR 561 CL:A novel combined antagonist of α-amino-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and volt-age-dependent sodium channels with anticonvulsive and Neuroprotective properties.J Pharmacol Exp.Ther,1999,289:1343-1349
[33]Nickel B,Shandra A,Godlevsky L.Anticonvulsant activity of D20443.Arch Pharmacol,1993,34.
[34]Cheney JA.Weisser JD.Bareyre FM.The maxi-K channel opener BMS-204352attenuates regional cerebral edema and neurologic motor impairment after experimental brain injury.J Cereb Blood Flow Metab,2001,21:396-403
[35]Jain KK.An assessment of ralinamide as an antiepileptic in comparision with other drugs in clinical development.Expert Opin Invetig Drugs,2000,9:829-40
[36]Fatope MO.Soretolide(Laboratories Bioeodex).Curr Opin Invetig Drugs,2001,2:824-7
[37]Chazot PL.Safinamide(Newron Pharmaceuticals).Curr Opin Invetig Drugs,2001:809-13
[38]Parsons AA,Bingham S,Raval P.Tonabersat(SB-220453) a novel be nzopyran with anticonvulsant prope rties attenuated trigeminal nerve-induced neurovascular reflexes.Br J Pharcol,1997,132:1549-57
[39]Bialer M,Johannessen SI,Kupferberg HJ.Progress report on new antiepileptic drugs:A summary of the fifth eliat conference(ELIAT V).Epilepsy Res,2001,43:11-58
[40]Hovinga CA.Novel anticonsultant medications in development.Epert Opin Investig Drugs,2002,11:1387-406
[41]Loscher W,Sehmidt D.New horizons in the development of antiepileptic drugs.Epilepsy Res,2002,50:3-16
[2]张庆松,抗癫痫药物的应用原则和治疗进展.医学导报,2000,19(15):421-3
[2]Leppik IE.Antiepileptic drugs in development:prospects for the near future.Epilepsia,1994,35,S4,29-40
[3]Nishi T,Kimura Y,Nakagawa K.Research and development of cilostazol:an ntiplatelet agent.Yakugaku Zasshi,2000,120,1247-60
[4]Perucca E.The new generation of antiepileptic drugs:advantages and disadvantages.Br J Clin Pharmacol,1996,42(5),531-43
[5]Joseph B,Darro F,Behard A,Lesur B,Collignon F,Decaestecker C,Frydman A,Guillaumet G,Kiss R.3-Aryl-2-quinolone derivatives:synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a newtherapeutical target connected with cell migration.J Med Chem,2002,45:2543-55
[6]Xiao Z,Waters NC,Woodard CL,Li Z,Li PK.Design and synthesis of Pfmrkinhibitors as potential anti-malarial agents.Bioorg Med Chem Lett,2001,11:2875-8
[7]Nishi T,Kimura Y,Nakagawa K.Research and development of cilostazol:an antiplatelet agent.Yakugaku Zasshi,2000,120:1247-60.
[8]Quan ZS.,Wang JM.,Lee WY.,Kwak KC.,Kang HC.,Chai KY.Synthesis of 6-alkyloxyl-3,4- dihydro-2(1H)-quinoliones and their Anticonvulsant Activities.Bull Kor Chem Soc,2005,26,1757-60
[9]Al-Soud YA,Al-Dweri MN,Al-Masoudi NA.Farmaco,2004,59:775-83.
[10]Labanauskas L,Udrenaite E,Gaidelis P,Brukstus A.Farmaco,2004,59:255-9
[11]Abak K,Sezer O,Akar A,Anac O.Eur J Med Chem,2003,38:215-8
[12]Gulerman NN,Dogan HN,Rollas S,Johansson C,Celik C Farmaco,2001,56:953-8
[13]Collin X,Sauleau A,Coulon J,Bioorg Med Chem Lett,2003,13:2601-5
[14]Cwiklicki A,Rehse K,Arch.Pharm(Weinheim),2004,337:156-63
[15]Cunha AC,Figueiredo JM,Tributino JL,Miranda AL,Castro HC,Zingali RB,Fraga CA,Souza MC,Ferreira VF,Barreiro EJ,Bioorg Med Chem,2003,11:2051-9
[16]Lazrek HB,Taourirte M,Oulih T,Barascut JL,Imbach JL,Pannecouque C,Witrouw M,De Clercq E.Nucleosides Nucleotides Nucleic Acids,2001,20:1949-60
[17]Kadaba PK.Curr Med Chem,2003.10:2081-108
[18]Kdaba PK,Stevenson PJ,P-Nnane I,Damani LA.Bioorg Med Chem,1996,4:65-78
[19]Kane JM,Baron BM,Dudley MW,Sorensen SM,Staeger MA,Miller FP.J Med Chem,1990,33:2772-7
[20]Cui LJ.,XieZF.,Piao HR.,Li G,Chai KY.,Quan ZS.Synthesis and anticonvulsant activity of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline.Biol Pharm Bull,2005,28,1216-20
[21]Xie ZF.,Chai KY.,Piao HR.,Kwak KC.,Quan ZS.Synthesis and anticonvulsant activity of 7-alkoxyl-4,5-dihydro-[1,2,4]triazole[4,3-a]quinolines.Bioorg Med Chem lett,2005,15,4803-5
[22]Jin HG,Sun XY,Chai XY,Piao HR,Quan ZS.Bioorg Med Chem,2006,Oct 15;14(20):6868-73
[23]Xian YS,Yun ZJ,Fu NL,Gao L,Kyu YC,and Zhe SQ.Arch Pharm Res,2006,29(12)1080-5
[24]Krall RJ.,Penry JK.,White BG.,Kupferberg HJ.Antiepileptic drug development:Ⅱ.Anticonvulsant drug screening.Epilepsia,1978,19,409-28
[25]Poter RJ.,Cereghino JJ.,Gladding GD.,Hessie BJ.,Kupferberg HJ.,Scoville B.Antiepileptic drug development program.Clev Clin J Med,1984,51,293-305
[1]Rodriguez-River L.Considerations on the concept of epilepsy.Rev Neurol,1999,28:1159-61
[2]Kumar R.Classification and the need to classify epilepsy.Indian J Pediatr,2000,67:S4-11
[3]Bell GS,Sander JW.The epidemiology of epilepsy:The size of problem.Seizure,2002,1:306-14
[4]Oun A,Haldre S,Magi M.Prevalence of adult epilepsy in Estonial.Epilepsy Res,2003;8:171-81
[5]Ducan JS.The promise of new antiepileptic drugs.Br J Clin Pharmacol,2002:53:123-31
[6]Selak I.Pregabalin(Pfizer).Curt Opin Investig Drugs,2001,2:828-34
[7]Taylor CP,Vartanian MG,Yuen PW.Potent and stereospeciflc anticonsul-tant activity of 3-isobutyl GABA relates to in vitrobinding at a novel site labeled by tritated gabapentin.Epilepsy Res,1993,14:11-5
[8]Whitworth TL,Quick MW.Upregulation of grama-aminobutyric acid transporter expession:Role of alkylated aminobutyric acid derivatives.Biochem Soc Trans,2001,29:736-41
[9]Hurley RW,Chatterjea D,Rose,Feng M.Gabapentin and Pregabalin can interact synergistically with naproxen to produce antihyperalgesial.Anesehesiology,2002,97:1263-76
[10]Huppertz HJ,Feuerstein TJ,Schulze-Bonhage A.Myoclonus in epilepsy patients with anticonvulsive add-on therapy with pregabalinl.Epilepsia,2001,42:790-792
[11]Cater RB,Wood PL,Wieland S.Characterization of anticonvulsant prop-erties of ganaxolone(CCd 1042;3a-hydroxy-313-metyhl-5a-pregnan-20-one),a selective,high-affinity.steroid modulator Of the aminobutyri acid receptor.J Pharmacol Exp Ther,1997,280:1285-95
[12]Gasior M,Cater RB,Goldberg SR.Anticonvulsant and behavioral effects of nueroactive steroids alone and in conianction with diazepaml.Pharmacol Exp Ther,1997,282:543-53
[13]Gasior M,Ungard JT,Beekman M.Acute and chronic efects of the synthetic neuroactive steroid,ganaxolone.against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice:Comparison with diazepam and volproate,Neurophar-maeology,2000,39:1184-96
[14]Reddy DS.Newer GABAergie agents for pharmaeyotherapy of infantilespasms. Drugs Today,2002,38:657-75
[15]Kaminski RM.Van Rijn CM.Turski WA.AMPA and GABAa receptor antagonist and their interaction an rats with a genetic form of absence epilepsy.Eur J Pharmaeol,2001,430:251-4
[16]Soudijn W.Wijingaarden I.The GABA transporter and its inhibitors.Curr Med Chem,2000,15:339-50
[17]Posson M,Huguet F,Sa vattier A.A new type of anticonvulsant,stiri-pentol.Pharmacological profile and neurochemieal study.Arzneim Forsch Drug Res,1984,34:199-204
[18]Karle J.Antisense studies of brain GABAa receptors.Dan Med Bull,2002,49:130-44
[19]Stavem K.Loge JH.Kassa S.Health status of people with epilepsy compared with a general reference population.Epilepsia,2000,41:85-90
[20]Gill R,AIanine A,Bourson A.Pharmacological eharacterization of Ro 63-1908(1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-meth-yl-benzyl)-piperidin-4-o 1) a novel subtype-selective N-methyl-D-aspartate antagonist.J Pharmacol Exp rher,2002,302:940-8
[21]Promk M,Castellino FJ.Structure-function relationships of the NMDA receptor antagonist conantokin peptides.Curt Drug Targets,2001,2:313-22
[22]Donevan SD,McCabe RT.Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors.Mol Pharmaeol,2000,58:614-23
[23]Jansen M,Potsehka H,Brandt C.Hydantoin substituted 4,6-dichloroindole-2-carboxylic acids as legends with high affinity for glyeine binding site of the NMDA receptor.J Med Chem,2003,46:64-73
[24]Srinivasan J.Richens A.Davies JA.The efect of losigamone(AO-33)on electrical activity and excitatory amino acid release in mouse cortical slices.Br J Pharmacol,1997,11:1490-4
[25]Gebhardt C,Breustedt JM,Noldner M.The antiepileptic drug losigamone decreases the persistent Na~+ current in rat hippocampal neurons.Brain Res,2001.920:27-31
[26]Bauer J,Schwalen S.Topiramate(TopamaxTM) Pharmacological characteristics and current use in epilepsy treatment.Nervenarzt,2000,71:495-501
[27]Tortorella A,Halonen T,Sanhibzada N.A crucial role of α-amino-3-hydroxy -5-methyl-isoxazole-4-propionic acid subtype of Glutamaterec--eptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures.J Pharmacol Exp Ther.,1997,280:1401-5
[28]Aubelson YP.Compititive AMPA an tagonism:A novel mechanism for anti-epileptic drugs.Drugs Fut,2001,26:463-71
[29]Borowicz KK.Kleinrok Z.Czucawar SJ.The AMPA/kainite receptor antagonist,LY300164,increases the anticonvulsant effects of diazepam.Arch Pharmacol,2000,361:629-635
[30]Lodge D,Bond A;o'Naill MJ.Stereoselective efects of 2.3-benzodiazepines invivo:Electrophysiology and neuroprotection studies.Nettropharmacology,1996.35:1681-8
[31]Ohno K,Tsutsumi R,Matsumoto N.Functional characterization of YM928,a novel non-competitive α-amino-3 hydroxy-5-methyl-4-isoxazoleprop ionic acid(AMPA)receptor antagonist.J Pharmacol Exp Ther,2003:303:66-72
[32]WeiserT,BrennerM,Palluk R.BⅡR 561 CL:A novel combined antagonist of α-amino-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and volt-age-dependent sodium channels with anticonvulsive and Neuroprotective properties.J Pharmacol Exp.Ther,1999,289:1343-1349
[33]Nickel B,Shandra A,Godlevsky L.Anticonvulsant activity of D20443.Arch Pharmacol,1993,34.
[34]Cheney JA.Weisser JD.Bareyre FM.The maxi-K channel opener BMS-204352attenuates regional cerebral edema and neurologic motor impairment after experimental brain injury.J Cereb Blood Flow Metab,2001,21:396-403
[35]Jain KK.An assessment of ralinamide as an antiepileptic in comparision with other drugs in clinical development.Expert Opin Invetig Drugs,2000,9:829-40
[36]Fatope MO.Soretolide(Laboratories Bioeodex).Curr Opin Invetig Drugs,2001,2:824-7
[37]Chazot PL.Safinamide(Newron Pharmaceuticals).Curr Opin Invetig Drugs,2001:809-13
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