Synthesis of nonimidazole H₃ receptor antagonists containing oxazole moiety and their antiseizure activity

Epilepsy is one of the most common neurological disorders and presents various obstacles to the fulfilling lives of people. Histamine H₃ receptors (H₃R) antagonists are becoming a promising therapeutic approach for epilepsy. In this paper, a series of novel nonimidazole H₃R antagonists have been designed, and synthesized. cAMP-response element (CRE) luciferase screening assay was used to evaluated their H₃R antagonistic activities. And their antiseizure activities were evaluated using the maximal electroshock seizure (MES)-induced seizure model. Among them, compounds 6a (IC₅₀ = 0.30 μM), 6c (IC₅₀ = 0.37 μM), 6f (IC₅₀ = 0.30 μM), 6m (IC₅₀ = 0.31 μM), and 6n (IC₅₀ = 0.35 μM) displayed the most potent H₃R antagonistic activities and exhibited high selectivity, without significant antagonistic activity against H₁R, H₂R, and H₄R. In the MES model, compounds 6a, 6c, 6f, 6m, and 6n showed varying degrees of protection for the electro-stimulated mice. Compound 6n was considered to be the most promising one, with an ED₅₀ values of 20.2 mg/kg. The antiseizure activity of 6a and 6n was also established in the PTZ-induced seizure model, with the ability to reduce the total movement distance significantly induced by PTZ. What's more, the protection of 6n against the MES-induced seizures was abrogated when mice were co-treated with RAMH, a CNS-penetrant H₃R agonist, which suggested that the potential therapeutic effect of 6n was through H₃R. Safety evaluation suggested that 6n has relatively lower cytotoxicity and neurotoxicity, although it shows hERG cardiotoxicity. Overall, this study provides a new source for antiseizure drug research whereby inhibiting H₃R is expected to yield new antiseizure drugs.