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Synthesis and antiseizure activity of ( E )-1,2-diarylethylidenehydrazine carboximidamides against tonic-clonic seizures: an intracerebroventricular and electrophysiological study
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2020-06-09 , DOI: 10.1007/s00044-020-02576-7
Fariba Abedi Firouzjaei , Elmira Heidarli , Shabnam Ravan , Sayed Masoud Hosseini , Nima Naderi , Kiarash Almasyan , Afshin Sarvary , Hamid Irannejad

A series of (E)-1,2-diarylethylidenehydrazine carboximidamides 2aj were synthesized and characterized by NOESY experiment as anticonvulsant agents and their antiseizure activity was evaluated by intracerebroventricular administration of compounds. Most of the compounds had significant protection against tonic-clonic seizures and 2a was found to be as equipotent as carbamazepine in seizures control. In order to find their anticonvulsant mechanism of action, 2a was subjected to further electrophysiological studies using patch-clamp technique. The results confirmed that this compound is neither a voltage-gated sodium channel blocker nor a NMDA/AMPA antagonist. Although 2a did not show any direct GABA agonistic activity, it could decrease EPSP and increase IPSP frequency without any change in amplitude. Finally, the results indicated most likely a presynaptic GABA-mediated mechanism of 2a for its antiseizure activity such as inhibition of the GABA-T which was validated by molecular docking.

中文翻译:

(E)-1,2-二芳基亚乙基肼羧咪嗪对强直阵挛性癫痫的合成及抗癫痫活性:脑室内和电生理研究

合成了一系列(E)-1,2-二芳基亚乙基肼羧酰亚胺化合物2aj,并通过NOESY实验将其表征为抗惊厥药,并通过脑室内给药来评估其抗癫痫活性。大多数化合物对强直-阵挛性癫痫发作具有显着的保护作用,在癫痫发作控制中发现2a与卡马西平同等。为了找到它们的抗惊厥作用机理,使用膜片钳技术对2a进行了进一步的电生理研究。结果证实该化合物既不是电压门控钠通道阻滞剂,也不是NMDA / AMPA拮抗剂。虽然2a没有显示出直接的GABA激动活性,它可以降低EPSP并增加IPSP频率,而幅度没有任何变化。最后,结果表明最有可能是突触前GABA介导的2a的抗癫痫活性机制,例如抑制GABA-T,这已通过分子对接验证。
更新日期:2020-06-09
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