Schwark W S, Löscher W
Naunyn Schmiedebergs Arch Pharmacol. 1985 Jun;329(4):367-71. doi: 10.1007/BF00496369.
Two novel, specific inhibitors of GABA uptake, namely SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid) and SKF 100330-A (N-[4,4-diphenyl-3-butenyl]-guvacine) were tested for anticonvulsant effects in amygdaloid kindled female rats. The anticonvulsant effectiveness of the compounds was compared with that of diazepam. SKF 89976-A and SKF 100330-A produced dose-dependent anticonvulsant effects on all seizure parameters measured in fully kindled rats, i.e. they inhibited seizure severity, increased seizure latency, and decreased the duration of motor seizures and EEG after discharges. ED 50s for inhibition of seizure severity were 4.6 and 15.1 mg/kg (0.014 and 0.045 mmol/kg) i.p. for SKF 100330-A and SKF 89976-A, respectively. For comparison, the ED 50 of diazepam was 1.9 mg/kg (0.0067 mmol/kg) i.p. Observation of behaviour indicated that the novel GABA uptake blockers exerted no side-effects in anticonvulsant doses, whereas diazepam produced sedative effects at all active dosage levels. The data demonstrate that SKF 100330-A and SKF 89976-A are potent, non-sedative anticonvulsant drugs in the kindling model of epilepsy, and these compounds thus may deserve interest as potential antiepileptic drugs with a very selective mechanism of action.
两种新型、特异性的γ-氨基丁酸（GABA）摄取抑制剂，即SKF 89976-A（N-[4,4-二苯基-3-丁烯基]-哌啶酸）和SKF 100330-A（N-[4,4-二苯基-3-丁烯基]-四氢烟酸），在杏仁核点燃的雌性大鼠中进行了抗惊厥作用测试。将这些化合物的抗惊厥效果与地西泮进行了比较。SKF 89976-A和SKF 100330-A对完全点燃大鼠所测量的所有癫痫发作参数均产生剂量依赖性抗惊厥作用，即它们抑制癫痫发作严重程度、延长癫痫发作潜伏期，并缩短运动性癫痫发作和脑电图放电后的持续时间。SKF 100330-A和SKF 89976-A腹腔注射抑制癫痫发作严重程度的半数有效剂量（ED50）分别为4.6和15.1mg/kg（0.014和0.045mmol/kg）。作为比较，地西泮的腹腔注射ED50为1.9mg/kg（0.0067mmol/kg）。行为观察表明，新型GABA摄取阻滞剂在抗惊厥剂量下无副作用，而地西泮在所有有效剂量水平均产生镇静作用。数据表明，在癫痫点燃模型中，SKF 100330-A和SKF 89976-A是有效的、无镇静作用的抗惊厥药物，因此这些化合物作为具有非常选择性作用机制的潜在抗癫痫药物可能值得关注。
