Anticonvulsant properties of histamine H3 receptor ligands belonging to N-substituted carbamates of imidazopropanol
| Autor: | Bassem Sadek, Mohamed Shafiullah, Safa Shehab, Małgorzata Więcek, Katarzyna Kieć-Kononowicz, Abdu Adem, Dhanasekaran Subramanian |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Phenytoin
medicine.medical_treatment Clinical Biochemistry Histamine Antagonists Pharmaceutical Science 1-Propanol Pharmacology Ligands Biochemistry Histamine Agonists chemistry.chemical_compound Seizures Drug Discovery medicine Animals Receptors Histamine H3 Inverse agonist Potency Rats Wistar Molecular Biology Electroshock Thioperamide Chemistry Organic Chemistry Imidazoles Antagonist Rats Anticonvulsant Molecular Medicine Anticonvulsants Carbamates Histamine H3 receptor Histamine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:4886-4891 |
| ISSN: | 0960-894X |
| Popis: | Ligands targeting central histamine H3 receptors (H3Rs) 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 H3R 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 (P0.05) than that of standard H3R antagonist THP, and was reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10mg/kg), or with the CNS penetrant H1R antagonist Pyrilamine (PYR) (10mg/kg). In addition, subeffective dose of H3R ligand 4 (5mg/kg, ip) significantly potentiated the protective action in rats pretreated with PHT (5mg/kg, ip), a dose without appreciable protective effect when given alone. In contrast, pretreatment with H3R ligand 4 (10mg/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 H3R ligands 1-13 may be of future therapeutic value in epilepsy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect