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A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (<b>1</b>&#8315;<b>16</b>) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist <b>4</b> shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist <b>13,</b> without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist <b>4</b> in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist (<i>R</i>)-&#945;-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist <b>4</b> in PTZ-induced seizure and H3R antagonist <b>13</b> in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound <b>4</b>. Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist <b>4</b> was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy.