Abstract
H(3)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(1H)-ones was prepared to screen their H(3)R antagonistic activities and antiseizure effects. The majority of the target compounds displayed a potent H(3)R antagonistic activity. Among them, compounds 2a, 2c, 2h, and 4a showed submicromolar H(3)R antagonistic activity with an IC(50) of 0.52, 0.47, 0.12, and 0.37 μM, respectively. The maximal electroshock seizure (MES) model screened out three compounds (2h, 4a, and 4b) 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 4a fully vanished when it was administrated combined with an H(3)R agonist (RAMH). These results showed that the antiseizure role of compound 4a might be achieved by antagonizing the H(3)R receptor. The molecular docking of 2h, 4a, and PIT with the H(3)R protein predicted their possible binding patterns and gave a presentation that 2h, 4a, and PIT had a similar binding model with H(3)R.