| Summary: | H<sub>3</sub>R is becoming an attractive and promising target for epilepsy treatment as well as the discovery of antiepileptics. In this work, a series of 6-aminoalkoxy-3,4-dihydroquinolin-2(1<i>H</i>)-ones was prepared to screen their H<sub>3</sub>R antagonistic activities and antiseizure effects. The majority of the target compounds displayed a potent H<sub>3</sub>R antagonistic activity. Among them, compounds <b>2a</b>, <b>2c</b>, <b>2h</b>, and <b>4a</b> showed submicromolar H<sub>3</sub>R antagonistic activity with an IC<sub>50</sub> of 0.52, 0.47, 0.12, and 0.37 μM, respectively. The maximal electroshock seizure (MES) model screened out three compounds (<b>2h</b>, <b>4a</b>, and <b>4b</b>) with antiseizure activity. Meanwhile, the pentylenetetrazole (PTZ)-induced seizure test gave a result that no compound can resist the seizures induced by PTZ. Additionally, the anti-MES action of compound <b>4a</b> fully vanished when it was administrated combined with an H<sub>3</sub>R agonist (RAMH). These results showed that the antiseizure role of compound <b>4a</b> might be achieved by antagonizing the H<sub>3</sub>R receptor. The molecular docking of <b>2h</b>, <b>4a</b>, and PIT with the H<sub>3</sub>R protein predicted their possible binding patterns and gave a presentation that <b>2h</b>, <b>4a</b>, and PIT had a similar binding model with H<sub>3</sub>R.
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