Wlaź P, Löscher W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Pharmacol. 1998 Jan 19;342(1):39-46. doi: 10.1016/s0014-2999(97)01452-0.
In the present work we evaluated the anticonvulsant effects of two novel antagonists of the glycine co-agonist site (glycineB receptor) within the N-methyl-D-aspartate (NMDA) receptor complex, MRZ 2/576 (a tricyclic pyrido-phtalazin dione derivative) and L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)quinoline). As a model of epilepsy we used amygdala-kindled rats, which are considered as a model to study the efficacy of drugs against human complex partial seizures. MRZ 2/576 (2.5-10 mg/kg i.p. 15 min before testing) did not influence afterdischarge threshold, which is believed to be the most subtle indicator of efficacy against kindled seizures, nor did it affect other measures of seizure activity such as seizure severity, seizure duration and afterdischarge duration. However, MRZ 2/576 produced dose-dependent ataxia as measured in the open field and rotarod test. The highest dose tested (10 mg/kg) also markedly reduced rectal temperature (by about 1.5 degrees C). L-701,324 (2.5-10 mg/kg i.p. 30 min before testing) dose dependently and significantly increased afterdischarge threshold, but other seizure parameters remained unchanged. The ataxia produced by lower doses of L-701,324 (2.5 and 5 mg/kg) was more pronounced than that caused by MRZ 2/576. However, the ataxia observed following the higher dose of L-701,324 (10 mg/kg) was less intense than that elicited by MRZ 2/576. The behavioral alterations produced by the two drugs did not resemble those characteristic for classical competitive and uncompetitive NMDA receptor antagonists. In conclusion, our data indicate that glycineB receptor antagonists are not promising candidates for the treatment of complex partial seizures in humans, at least as monotherapy.
在本研究中，我们评估了N-甲基-D-天冬氨酸（NMDA）受体复合物中甘氨酸协同激动剂位点（甘氨酸B受体）的两种新型拮抗剂MRZ 2/576（一种三环吡啶并酞嗪二酮衍生物）和L-701,324（7-氯-4-羟基-3-(3-苯氧基)苯基-2(H)喹啉）的抗惊厥作用。作为癫痫模型，我们使用了杏仁核点燃大鼠，其被视为研究药物抗人类复杂部分性发作疗效的模型。MRZ 2/576（在测试前15分钟腹腔注射2.5 - 10毫克/千克）不影响放电后阈值（据信这是抗点燃性癫痫发作疗效的最微妙指标），也不影响癫痫发作活动的其他指标，如癫痫发作严重程度、发作持续时间和放电后持续时间。然而，则在旷场试验和转棒试验中，MRZ 2/576产生了剂量依赖性共济失调。测试的最高剂量（10毫克/千克）也显著降低了直肠温度（约1.5摄氏度）。L-701,324（在测试前30分钟腹腔注射2.5 - 10毫克/千克）剂量依赖性且显著提高了放电后阈值，但其他癫痫发作参数保持不变。较低剂量的L-701,（2.5和5毫克/千克）所产生的共济失调比MRZ 2/576引起的更明显。然而，较高剂量的L-701,324（10毫克/千克）后观察到的共济失调比MRZ 2/576引起者较轻。这两种药物产生的行为改变与经典竞争性和非竞争性NMDA受体拮抗剂的特征不同。总之，我们的数据表明，甘氨酸B受体拮抗剂不是治疗人类复杂部分性发作的有前景的候选药物，至少作为单一疗法时不是。
