Anticonvulsant activity of 2,4(1H)-diarylimidazoles in mice and rats acute seizure models

Abstract

2,4(1H)-Diarylimidazoles have been previously shown to inhibit hNa(V)1.2 sodium (Na) channel currents. Since many of the clinically used anticonvulsants are known to inhibit Na channels as an important mechanism of their action, these compounds were tested in two acute rodent seizure models for anticonvulsant activity (MES and scMet) and for sedative and ataxic side effects. Compounds exhibiting antiepileptic activity were further tested to establish a dose response curve (ED(50)). The experimental data identified four compounds with anticonvulsant activity in the MES acute seizure rodent model (compound 10, ED(50)=61.7mg/kg; compound 13, ED(50)=46.8mg/kg, compound 17, ED(50)=129.5mg/kg and compound 20, ED(50)=136.7mg/kg). Protective indexes (PI=TD(50)/ED(50)) ranged from 2.1 (compound 10) to greater than 3.6 (compounds 13, 17 and 20). All four compounds were shown to inhibit hNa(V)1.2 in a dose dependant manner. Even if a correlation between sodium channel inhibition and anticonvulsant activity was unclear, these studies identify four Na channel antagonists with anticonvulsant activity, providing evidence that these derivatives could be potential drug candidates for development as safe, new and effective antiepileptic drugs (AEDs).

Figure 1

Na channel blockers.

Figure 2

Inhibition of hNav1.2 Na channel currents by active compounds. Na channel currents shown were elicited by a step depolarization to +10 mV from a holding potential of −60 mV for 12 ms.

Scheme 1

Synthesis of the 2,4(1H)-diarylimidazoles 3–29 Reagents and Conditions: 1 equiv. 1 in 3.8 mL CH₃OH; 1 equiv. 2 and 4 equiv. CH₃COONH₄ in 3.5 mL CH₃OH. Overnight at r.t..