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Synthesis and antiseizure activity of (E)-1,2-diarylethylidenehydrazine carboximidamides against tonic-clonic seizures: an intracerebroventricular and electrophysiological study

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Abstract

A series of (E)-1,2-diarylethylidenehydrazine carboximidamides 2a–j 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.

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Acknowledgements

This work was supported in part by a grant from Mazandaran University of Medical Sciences (grant No. 1796) and also by grant from Shahid Beheshti University of Medical Sciences (grant No. 9487).

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Babol Noshirvani University of Technology, Babol, Iran

    Fariba Abedi Firouzjaei & Afshin Sarvary

  2. Department of Pharmacology & Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Elmira Heidarli, Shabnam Ravan, Sayed Masoud Hosseini & Nima Naderi

  3. Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Kiarash Almasyan & Hamid Irannejad

  4. Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Hamid Irannejad

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  1. Fariba Abedi Firouzjaei
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  2. Elmira Heidarli
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  4. Sayed Masoud Hosseini
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Correspondence to Nima Naderi or Hamid Irannejad.

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Firouzjaei, F.A., Heidarli, E., Ravan, S. et al. Synthesis and antiseizure activity of (E)-1,2-diarylethylidenehydrazine carboximidamides against tonic-clonic seizures: an intracerebroventricular and electrophysiological study. Med Chem Res 29, 1520–1535 (2020). https://doi.org/10.1007/s00044-020-02576-7

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