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.

Antiseizure; Epilepsy; H(3) receptor antagonists; Oxazole.