Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage-gated sodium channels.
Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage-gated sodium channels.
复制标题
抗癫痫药物拉科酰胺新型衍生物的开发和表征，其对电压门控钠通道的缓慢失活表现出更大的增强作用。
DOI：
10.1021/cn100089b
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发表时间：
2011
影响因子：
5
通讯作者：
Kohn,Harold
中科院分区：
文献类型：
--
作者：
Wang,Yuying;Park,KiDuk;Salome,Christophe;Wilson,SarahM;Stables,JamesP;Liu,Rihe;Khanna,Rajesh;Kohn,Harold
新型抗癫痫药物（R）-N-苄基2-乙酰氨基-3-甲氧基丙酰胺（（R）-拉考沙胺，Vimpat（（R）-1））最近在美国和欧洲获批用于成人部分性癫痫发作的辅助治疗。（R）-1优先增强电压门控Na+电流的缓慢失活，这是一个与过度兴奋神经元相关的药理学过程。我们已经提出了一种通过将亲和诱饵（AB）和化学报告（CR）基团连接到（R）-1上以辅助受体检测和分离来鉴定拉考沙胺结合伴侣的策略。在啮齿类动物最大电休克模型中，我们发现所选的拉考沙胺AB和AB&CR衍生物显示出与（R）-1相似的优良活性。在此，我们研究了这些拉考沙胺AB和AB&CR衍生物对中枢神经系统（CNS）儿茶酚胺能（CAD）细胞Na+通道功能的影响，并与（R）-1进行了比较。使用全细胞膜片钳电生理学，我们证明了测试化合物不影响Na+通道快速失活过程，它们是比（R）-1更好的慢失活调节剂，并且慢失活过程的调节是立体特异性的。AB激活后，含有亲电异硫氰酸酯（（R）-5）或光不稳定叠氮化物（（R）-8）单元的拉考沙胺AB试剂产生了适度水平的永久性Na+通道缓慢失活，提供了这些化合物可能与其同源受体发生共价反应的初步证据。我们的研究结果支持进一步使用这些药物来描绘（R）-1介导的Na+通道缓慢失活过程。
The novel antiepileptic drug (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide, Vimpat ((R)-1)) was recently approved in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. (R)-1preferentially enhances slow inactivation of voltage-gated Na+currents, a pharmacological process relevant in the hyperexcitable neuron. We have advanced a strategy to identify lacosamide binding partners by attaching affinity bait (AB) and chemical reporter (CR) groups to (R)-1to aid receptor detection and isolation. We showed that select lacosamide AB and AB&CR derivatives exhibited excellent activities similar to (R)-1in the maximal electroshock seizure model in rodents. Here, we examined the effect of these lacosamide AB and AB&CR derivatives and compared them with (R)-1on Na+channel function in central nervous system (CNS) catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demonstrated that the test compounds do not affect the Na+channel fast inactivation process, that they were far better modulators of slow inactivation than (R)-1,and that modulation of the slow inactivation process was stereospecific. The lacosamide AB agents that contained either an electrophilic isothiocyanate ((R)-5) or a photolabile azide ((R)-8) unit upon AB activation gave modest levels of permanent Na+channel slow inactivation, providing initial evidence that these compounds may have covalently reacted with their cognate receptor(s). Our findings support the further use of these agents to delineate the (R)-1-mediated Na+channel slow inactivation process.