Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: Relationship to anti-convulsant properties
Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: Relationship to anti-convulsant properties
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DOI：
10.1016/j.ejphar.2011.04.064
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发表时间：
2011-08-16
影响因子：
5
通讯作者：
Matagne, Alain
中科院分区：
文献类型：
--
作者：
Gillard, Michel;Fuks, Bruno;Matagne, Alain
布列伐西坦是一种新的突触囊泡蛋白2A(SV2A)配体，据报道在癫痫动物模型中的效力是左乙拉西坦的10倍。通过大鼠、人脑、小鼠脑内和重组人SV2a的体外结合实验，测定了布里伐西坦及其氚化体[(3)H]UCB 34714的亲和力、动力学和选择性。比较了布里伐西坦和左乙拉西坦与SV2A的体外结合以及对听性小鼠的抗惊厥活性，结果表明，布里伐西坦选择性结合SV2A的亲和力是左乙拉西坦的20倍。[(3)H]UCB 34714可逆地与大鼠和人脑中均一组结合部位结合，并与CHO细胞表达的人SV2a结合，亲和力高。[(3)H]UCB 34714标记的结合部位在脑内具有Sv2A型的药理学特征，在Sv2A型(-/-)基因敲除小鼠的脑内未检测到特异性结合。布里伐西坦和左乙拉西坦与脑部SV2A结合并在听源性小鼠中提供癫痫保护的时间和剂量依赖性很好；布里瓦西坦比左乙拉西坦更有效、更快。布里瓦西坦是一种有效和选择性的SV2A配体。根据其亲和力和药代动力学，模拟预测，在治疗相关剂量下，布伐拉西坦在人脑中应占据SV2A的80%以上，与临床前癫痫模型中观察到的水平一致。(C)2011爱思唯尔B.V.保留所有权利。
Brivaracetam is a novel synaptic vesicle protein 2A (SV2A) ligand reported to be 10 fold more potent than levetiracetam in animal models of epilepsy. This study reports the binding profile of brivaracetam in the brain of several species in relation to its anticonvulsant properties.The affinity, kinetics and selectivity of brivaracetam and its tritiated form [(3)H]ucb 34714 have been determined by in vitro binding experiments in rat, human and mouse brain and on recombinant human SV2A. Brivaracetam and levetiracetam ex vivo binding to SV2A and anticonvulsant activities in audiogenic mice were compared in relation to dose and time.Brivaracetam bound selectively with 20 fold higher affinity than levetiracetam to SV2A. [(3)H]ucb 34714 bound reversibly and with high affinity to an homogenous population of binding sites in rat and human brain and to human SV2A expressed in CHO cells. The binding sites labeled by [(3)H]ucb 34714 in brain had the pharmacological characteristics of SV2A and no specific binding could be detected in the brain of SV2A(-/-) knock-out mice. The time- and dose-dependency of brivaracetam and levetiracetam for binding to brain SV2A and for providing seizure protection in audiogenic mice correlated well; brivaracetam being more potent and faster than levetiracetam.Brivaracetam is a potent and selective SV2A ligand. From its affinity and pharmacokinetics, simulations predicted that at therapeutically relevant doses, brivaracetam should occupy more than 80% of SV2A in human brain, in line with levels of occupancy observed in pre-clinical models of epilepsy. (C) 2011 Elsevier B.V. All rights reserved.