Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.
To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics.
aDepartment of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates bDepartment of Technology and Biotechnology of Drugs, Medical College, Faculty of Pharmacy, Jagiellonian University, Kraków, Poland cInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University, Düsseldorf, Germany.
Bassem
B
Sadek
Kamil
K
Kuder
Dhanasekaran
D
Subramanian
Mohamed
M
Shafiullah
Holger
H
Stark
Dorota
D
Lażewska
Abdu
A
Adem
Katarzyna
K
Kieć-Kononowicz
D000465:Algorithms; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology; D054828:Histamine H3 Antagonists / Q000627:therapeutic use*; D008297:Male; D010433:Pentylenetetrazole / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects
D000927:Anticonvulsants; D003292:Convulsants; D054828:Histamine H3 Antagonists; D010433:Pentylenetetrazole