Suzdak P D, Jansen J A
Department of Neurobiology, Novo Nordisk, Malov, Denmark.
Epilepsia. 1995 Jun;36(6):612-26. doi: 10.1111/j.1528-1157.1995.tb02576.x.
We review the neurochemical and behavioral profile of the selective gamma-aminobutyric acid (GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy. TGB is a potent, and specific GABA uptake inhibitor. TGB lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous GABA. In vivo microdialysis shows that TGB also increases extracellular GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent anticonvulsant agent against methyl-6,7-dimethyoxy-4-ethyl-B-carboline-3-carboxylate (DMCM)-induced clonic convulsions (mice), subcutaneous pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious, against subcutaneous PTZ-induced clonic convulsions, and photically induced myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against bicuculline (BIC)-induced convulsions in rats. The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic-tonic epilepsy (GTCS), photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.
我们综述了选择性γ-氨基丁酸（GABA）摄取抑制剂（R）-N-（4,4-二-（3-甲基噻吩-2-基）丁-3-烯基）盐酸尼哌酸[噻加宾（TGB），以前称为NNC 05-0328、NO 05-0328和NO-328]的神经化学和行为特征，该药物目前正处于癫痫的III期临床试验阶段。TGB是一种强效且特异性的GABA摄取抑制剂。TGB对其他神经递质受体结合位点和/或摄取位点缺乏显著亲和力。在培养的海马切片的电生理实验中，TGB延长了添加外源性GABA后在CA1和CA3产生的抑制性突触后电位（IPSP）和抑制性突触后电流（IPSC）。体内微透析表明，TGB也以剂量依赖性方式增加细胞外GABA的溢出。这些生化数据共同表明，TGB在体外和体内的作用机制是特异性抑制GABA摄取，导致大脑中GABA能介导的抑制作用增强。TGB是一种强效抗惊厥剂，可对抗甲基-6,7-二甲氧基-4-乙基-β-咔啉-3-羧酸酯（DMCM）诱导的阵挛性惊厥（小鼠）、皮下注射戊四氮（PTZ）诱导的强直性惊厥（小鼠和大鼠）、DBA/2小鼠和遗传性癫痫易感大鼠（GEPR）的声音诱导惊厥以及点燃大鼠的电诱导惊厥。TGB对皮下注射PTZ诱导的阵挛性惊厥以及狒狒的光诱导肌阵挛部分有效。TGB在静脉注射PTZ惊厥阈值试验和最大电休克惊厥（MES）试验中效力较弱，并且仅对大鼠荷包牡丹碱（BIC）诱导的惊厥产生部分保护作用。TGB的整体生化和抗惊厥特征表明其在治疗慢性癫痫疾病如全身性阵挛-强直性癫痫（GTCS）、光肌阵挛性癫痫、肌阵挛性小发作癫痫和复杂部分性癫痫方面具有潜在用途。
