Swinyard E A, Wolf H H, White H S, Skeen G A, Stark L G, Albertson T, Pong S F, Drust E G
Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City 84112.
Epilepsy Res. 1993 May;15(1):35-45. doi: 10.1016/0920-1211(93)90007-t.
The anticonvulsant properties of F-721 (3-diethylamino-2,2-dimethylpropyl-5-[p-trifluoromethylphenyl]-2-f uroate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N-methyl-D-aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures (ED50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhibited only partial activity against clonic seizures induced in the subcutaneous Metrazol and subcutaneous bicuculline test in mice and was inactive in this species against tonic seizures induced in the subcutaneous strychnine test. F-721 was effective against MES seizures following oral administration to mice (ED50: 31.3 mg/kg) and only partially effective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal electroshock model following oral administration (ED50: 9.9 mg/kg). F-721 was also effective against corneal-kindled and amygdaloid-kindled seizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kindled rats at doses that did not cause sedation or ataxia. At 40 mg/kg, F-721 reduced afterdischarge duration by 83.2% and reduced the seizure severity score to 1.7. The ED50 for 50% reduction of afterdischarge duration was 16.3 mg/kg, ip. In cultured mouse spinal cord neurons, F-721 suppressed sustained repetitive firing in response to a depolarizing current with a median inhibitory concentration (IC50) of 1.9 microM. F-721 had no effect on adenosine uptake, gamma-aminobutyric acid or NMDA receptor binding. Comparative data from previous studies with clinically established antiepileptic agents reveal that F-721's profile of activity most closely resembles that of phenytoin and carbamazepine. However, F-721 was notably more efficacious in suppressing amygdaloid-kindled seizures in rats and was a more potent antagonist of icv NMDA clonic seizures. Our studies indicate that F-721 is a potent, orally active anticonvulsant with a favorable margin of safety. The profile of anticonvulsant activity of F-721 suggests potential utility in the management of generalized tonic-clonic, simple and complex partial seizures.
在一系列体内和体外抗惊厥模型系统中研究了F - 721（盐酸3 - 二乙氨基 - 2,2 - 二甲基丙基 - 5 - [对 - 三氟甲基苯基] - 2 - 呋喃酯）的抗惊厥特性。给小鼠腹腔注射后，F - 721以无毒剂量对最大电休克（MES）、皮下注射印防己毒素阵挛性发作、脑室内（icv）注射N - 甲基 - D - 天冬氨酸（NMDA）强直性发作、icv注射NMDA阵挛性发作和icv注射喹啉酸强直性发作有效（半数有效剂量[ED50]分别为：11.1、28.4、1.76、3.4和4.4毫克/千克）。F - 721在小鼠皮下注射戊四氮和皮下注射荷包牡丹碱试验中诱导的阵挛性发作仅表现出部分活性，并且在该物种中对皮下注射士的宁试验诱导的强直性发作无活性。给小鼠口服后，F - 721对MES发作有效（ED50：31.3毫克/千克），通过该途径对皮下注射戊四氮诱导的阵挛性发作仅部分有效。在大鼠中，口服F - 721在最大电休克模型中是一种有效的抗惊厥药（ED50：9.9毫克/千克）。F - 721对大鼠角膜点燃和杏仁核点燃性发作也有效。F - 721以15毫克/千克腹腔注射抑制角膜点燃大鼠的5期发作。此外，在不引起镇静或共济失调的剂量下，它还能缩短杏仁核点燃大鼠的放电后持续时间并降低行为性发作阶段。在40毫克/千克时，F - 721使放电后持续时间缩短83.2%，并将发作严重程度评分降至1.7。使放电后持续时间减少50%的ED50为16.3毫克/千克腹腔注射。在培养的小鼠脊髓神经元中，F - 721抑制对去极化电流的持续重复放电，中位抑制浓度（IC50）为1.9微摩尔。F - 721对腺苷摄取、γ - 氨基丁酸或NMDA受体结合无影响。来自先前对临床已确立的抗癫痫药物研究的比较数据表明，F - 721的活性谱与苯妥英和卡马西平最为相似。然而，F - 721在抑制大鼠杏仁核点燃性发作方面明显更有效，并且是icv注射NMDA阵挛性发作的更强效拮抗剂。我们的研究表明，F - 721是一种有效的口服活性抗惊厥药，具有良好的安全范围。F - 721的抗惊厥活性谱表明其在全身性强直 - 阵挛性发作、简单和复杂部分性发作的治疗中具有潜在用途。
