Design, synthesis, and anticonvulsant effects evaluation of nonimidazole histamine H(3) receptor antagonists/inverse agonists containing triazole moiety

Histamine H(3) receptors (H(3)R) antagonists/inverse agonists are becoming a promising therapeutic approach for epilepsy. In this article, novel nonimidazole H(3)R antagonists/inverse agonists have been designed and synthesised via hybriding the H(3)R pharmacophore (aliphatic amine with propyloxy chain) with the 1,2,4-triazole moiety as anticonvulsant drugs. The majority of antagonists/inverse agonists prepared here exerted moderate to robust activities in cAMP-response element (CRE) luciferase screening assay. 1-(3-(4-(3-Phenyl-4H-1,2,4-triazol-4-yl)phenoxy)propyl)piperidine (3l) and 1-(3-(4-(3-(4-chlorophenyl)-4H-1,2,4-triazol-4-yl)phenoxy)propyl)piperidine (3m) displayed the highest H(3)R antagonistic activities, with IC(50) values of 7.81 and 5.92 nM, respectively. Meanwhile, the compounds with higher H(3)R antagonistic activities exhibited protection for mice in maximal electroshock seizure (MES)-induced convulsant model. Moreover, the protection of 3m against the MES induced seizures was fully abrogated when mice were co-treated with RAMH, a CNS-penetrant H(3)R agonist, which suggested that the potential therapeutic effect of 3m was through H(3)R. These results indicate that the attempt to find new anticonvulsant among H(3)R antagonists/inverse agonists is practicable.