Potschka H, Löscher W, Wlaź P, Behl B, Hofmann H P, Treiber H J, Szabo L
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Br J Pharmacol. 1998 Nov;125(6):1258-66. doi: 10.1038/sj.bjp.0702172.
The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.
本研究的目的是评估一种同时对NMDA和非NMDA受体具有拮抗作用的药物，与仅拮抗这些离子型谷氨酸受体之一的药物相比，在治疗癫痫发作方面是否具有优势。新型谷氨酸受体拮抗剂LU 73068（4,5-二氢-1-甲基-4-氧代-7-三氟甲基咪唑并[1,2a]喹喔啉-2-碳酸）与NMDA受体的甘氨酸位点（Ki 185 nM）和AMPA受体（Ki 158 nM）均具有高亲和力结合。此外，用重组海人酸受体亚基进行的结合实验表明，LU 73068与其中几个亚基结合，特别是与rGluR7（Ki 104 nM）和rGluR5（Ki 271 nM）结合。相比之下，原型非NMDA受体拮抗剂NBQX（2,3-二羟基-6-硝基-7-氨磺酰基-苯并[f]喹喔啉）仅与AMPA受体具有高亲和力结合。腹腔注射后，NBQX和LU 73068在小鼠中阻断由AMPA或NMDA诱导的致死性惊厥的效果大致相当。在大鼠颞叶癫痫的杏仁核点燃模型中，LU 73068剂量依赖性地提高局灶性癫痫发作阈值（后放电阈值，ADT）。当用高于个体对照ADT 20%的电流刺激大鼠时，LU 73068以4.9 mg·kg⁻¹的ED50完全阻断癫痫发作。高达20 mg·kg⁻¹时，仅观察到中度不良反应，如轻微共济失调。单独给药时，10 mg·kg⁻¹的NBQX和2.5或5 mg·kg⁻¹的甘氨酸/NMDA位点拮抗剂L-701,324（7-氯-4-羟基-3-(3-苯氧基)苯基-喹啉-2(1H)酮）在点燃大鼠中没有抗惊厥作用，但两种药物联合治疗导致ADT显著升高。数据表明，在单一药物中联合甘氨酸/NMDA和非NMDA受体拮抗作用是开发一种强效且有效的抗惊厥药物的有效手段。
