Inhibition of neuronal Na+ channels by the novel antiepileptic compound DCUKA: identification of the diphenylureido moiety as an inactivation modifier.
Inhibition of neuronal Na+ channels by the novel antiepileptic compound DCUKA: identification of the diphenylureido moiety as an inactivation modifier.
复制标题
新型抗癫痫化合物 DCUKA 对神经元 Na 通道的抑制：鉴定二苯基脲基部分作为失活修饰剂。
DOI：
10.1006/exnr.2002.8029
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发表时间：
2002
影响因子：
5.3
通讯作者：
Levinson,SimonR
中科院分区：
文献类型：
--
作者：
Wang,Ze-Jun;Snell,LawrenceD;Tabakoff,Boris;Levinson,SimonR
在先前对现有抗癫痫化合物的分析中，我们提出共同的二苯基脲基部分负责这些药物的活性依赖性Na+通道阻断作用（L. D. Snell等人，2000，J. Pharmacol. Exp. Ther. 292：215-227）。因此，开发了新的二苯基脲基化合物[N，N-（二苯基）-4-脲基-5，7-二氯-2-羧基喹啉] DCUKA，以将二苯基脲基药效团掺入也作为NMDA受体拮抗剂的结构中。DCUKA以前已被证明具有抗癫痫性质的动物，在本研究中的行动DCUKA对Na+电流的特点是使用转染细胞，稳定表达大鼠脑Nav1.2通道亚型。在全细胞电压钳记录中，DCUKA以剂量和膜电位依赖性方式降低Na+电流，药物与通道相互作用的化学计量比明显为1：1。DCUKA对Na+通道功能影响的表征强烈表明DCUKA通过增强Na+通道失活而起作用。因此，在存在DCUKA的情况下，Nav1.2通道在稳态失活方案中显示出降低的可用性，显示出使用依赖性抑制，并且从失活中恢复的速度比未处理的通道慢，而DCUKA显示出与通道的开放状态没有显著的相互作用。正如以前假设的抗惊厥药卡马西平和苯妥英，这些结果可以很好地解释了一个模型，其中药物优先与通道的快速失活状态的相互作用。最后，DCUKA在改变钠通道行为方面通常比卡马西平更有效。因此，通过经典抗惊厥药的结构分析确定的二苯基脲基部分似乎对这类抗惊厥药的失活特异性Na+通道抑制很重要。
In a previous analysis of existing antiseizure compounds, we suggested that a common diphenylureido moiety was responsible for the activity-dependent, Na+channel blocking actions of these drugs (L. D. Snell et al., 2000, J. Pharmacol. Exp. Ther. 292: 215–227). Thus the novel diphenylureido compound [N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyquinoline] DCUKA was developed to incorporate the diphenylureido pharmacophore into a structure that also acted as an NMDA receptor antagonist. DCUKA has previously been shown to have antiepileptic properties in animals, and in the present study the actions of DCUKA on Na+currents were characterized using transfected cells that stably expressed the rat brain Nav1.2 channel isoform. In whole-cell voltage-clamp recordings, DCUKA reduced Na+currents in a dose- and membrane potential-dependent fashion, with an apparent 1:1 stoichiometry of drug:channel interaction. Characterization of the effects of DCUKA on Na+channel function strongly suggested that DCUKA acts by enhancing Na+channel inactivation. Thus in the presence of DCUKA, Nav1.2 channels showed reduced availability in steady-state inactivation protocols, displayed use-dependent inhibition, and were slower to recover from inactivation than untreated channels, while DCUKA showed no significant interaction with the open state of the channel. As previously postulated for the anticonvulsants carbamazepine and phenytoin, these results could be well explained by a model in which the drug preferentially interacts with the fast inactivated state of the channel. Finally, DCUKA was generally more efficacious than carbamazepine in modifying sodium channel behavior. Thus the diphenylureido moiety identified by a structural analysis of classic anticonvulsants appears to be important to the inactivation-specific Na+channel inhibition by this class of antiseizure agents.