Anticonvulsant properties of histamine H3 receptor ligands belonging to N-substituted carbamates of imidazopropanol

Bassem Sadek, Safa Shehab, Małgorzata Wiȩcek, Dhanasekaran Subramanian, Mohamed Shafiullah, Katarzyna Kieć-Kononowicz, Abdu Adem

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25 Scopus citations


Ligands targeting central histamine H3 receptors (H 3Rs) for epilepsy might be a promising therapeutic approach. Therefore, the previously described and structurally strongly related imidazole-based derivatives belonging to carbamate class with high H 3R in vitro affinity, in-vivo antagonist potency, and H3R selectivity profile were investigated on their anticonvulsant activity in maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in Wistar rats. The effects of systemic injection of H3R ligands 1-13 on MES-induced and PTZ-kindled seizures were screened and evaluated against the reference antiepileptic drug (AED) Phenytoin (PHT) and the standard histamine H3R inverse agonist/antagonist Thioperamide (THP) to determine their potential as new antiepileptic drugs. Following administration of the H3R ligands 1-13 (5, 10 and 15 mg/kg, ip) there was a significant dose dependent reduction in MES-induced seizure duration. The protective action observed for the pentenyl carbamate derivative 4, the most protective H3R ligand among 1-13, was significantly higher (P <0.05) than that of standard H3R antagonist THP, and was reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg), or with the CNS penetrant H 1R antagonist Pyrilamine (PYR) (10 mg/kg). In addition, subeffective dose of H3R ligand 4 (5 mg/kg, ip) significantly potentiated the protective action in rats pretreated with PHT (5 mg/kg, ip), a dose without appreciable protective effect when given alone. In contrast, pretreatment with H3R ligand 4 (10 mg/kg ip) failed to modify PTZ-kindled convulsion, whereas the reference drug PHT was found to fully protect PTZ-induced seizure. These results indicate that some of the investigated imidazole-based H 3R ligands 1-13 may be of future therapeutic value in epilepsy.

Original languageBritish English
Pages (from-to)4886-4891
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Issue number17
StatePublished - 1 Sep 2013


  • Carbamate derivatives
  • HR ligands
  • Imidazopropanol
  • Protective effect
  • Seizures


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