Antiseizure Properties of Histamine H3 Receptor Antagonists Belonging 3,4-Dihydroquinolin-2(1H)-Ones

Abstract

H3R 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 H3R antagonistic activities and antiseizure effects. The majority of the target compounds displayed a potent H3R antagonistic activity. Among them, compounds 2a, 2c, 2h, and 4a showed submicromolar H3R antagonistic activity with an IC50 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 H3R agonist (RAMH). These results showed that the antiseizure role of compound 4a might be achieved by antagonizing the H3R receptor. The molecular docking of 2h, 4a, and PIT with the H3R protein predicted their possible binding patterns and gave a presentation that 2h, 4a, and PIT had a similar binding model with H3R.

Reproductive and fetal toxicity studies of histamine H3 receptor antagonist DL76 used in mice to prevent maximal electroshock-induced seizure

“…In a very recent study, a group of compounds known as 6-aminoalkoxy-3,4-dihydroquinolin-2(1H)-ones were synthesized to evaluate their potential as H3R antagonists and their ability to prevent seizures ( Hua et al, 2023 ). The synthesized compounds exhibited strong H3R antagonism.…”

“…Molecular docking studies involving compounds 2h, 4a, and a reference compound PIT with the H3R protein were conducted to predict how these molecules might interact with the H3R binding site. The docking results indicated that 2h, 4a, and PIT likely share a similar binding mode to the H3R, providing insights into the molecular basis for their antagonistic effects ( Hua et al, 2023 ).…”

“…As previously described and with a slight modification in the intensity applied, seizures were elicited in mice with a 50-Hz alternating current of 120 mA intensity ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ). The current was applied through ear electrodes for 0.2 s. Protection against the spread of MES-induced convulsion was defined as the abolition of the tonic hind limb extension (THLE) component of the seizure ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ).…”

“…As previously described and with a slight modification in the intensity applied, seizures were elicited in mice with a 50-Hz alternating current of 120 mA intensity ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ). The current was applied through ear electrodes for 0.2 s. Protection against the spread of MES-induced convulsion was defined as the abolition of the tonic hind limb extension (THLE) component of the seizure ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ). The animals were divided into the following experimental groups, with eight mice in each: the control group injected with saline, the positive control group injected with 300 mg/kg of VPA (the minimal dose of VPA that protected animals against the spread of MES-induced convulsions without mortality in mice) ( Sadek et al, 2015 ; Bastaki et al, 2018 ), and four groups that were administered the test compound DL76 at doses of 7.5 mg/kg, 15 mg/kg, 30 mg/kg, or 60 mg/kg.…”