Anticonvulsant properties of histamine H3 receptor ligands belonging to N-substituted carbamates of imidazopropanol |
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Authors: | Bassem Sadek Safa Shehab Małgorzata Więcek Dhanasekaran Subramanian Mohamed Shafiullah Katarzyna Kieć-Kononowicz Abdu Adem |
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Affiliation: | 1. Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, PO Box 17666, United Arab Emirates;2. Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, PO Box 17666, United Arab Emirates;3. Jagiellonian University-Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9 St., 30-688 Kraków, Poland |
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Abstract: | 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 (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 H1R 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 H3R ligands 1–13 may be of future therapeutic value in epilepsy. |
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Keywords: | Imidazopropanol Carbamate derivatives Protective effect Seizures |
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