title: Anticonvulsant properties of histamine H3 receptor ligands belonging to N-substituted carbamates of imidazopropanol.
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) (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.
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, PO Box 17666, United Arab Emirates. bassem.sadek@uaeu.ac.ae
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.forename: Safa
authors.initials: S
authors.lastname: Shehab
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Więcek
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Subramanian
authors.forename: Mohamed
authors.initials: M
authors.lastname: Shafiullah
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
authors.forename: Abdu
authors.initials: A
authors.lastname: Adem
mesh_terms: D000433:1-Propanol / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000627:therapeutic use*; D002219:Carbamates / Q000737:chemistry* / Q000627:therapeutic use*; D004597:Electroshock; D017442:Histamine Agonists; D006633:Histamine Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use; D008024:Ligands; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D018100:Receptors, Histamine H3; C029899:imidazole; D000433:1-Propanol
keywords: Carbamate derivatives; H(3)R ligands; Imidazopropanol; Protective effect; Seizures