Anticonvulsant and antiepileptogenic effects of azolylchromanones on lithium-pilocarpine induced seizures and pentylenetetrazole-kindling model of epilepsy.

Abstract

Recently, we described the design and synthesis of azolylchroman derivatives as conformationally constrained analogs of (arylalkyl)azole anticonvulsants. In the present study, two distinct pharmacological models, lithium-pilocarpine induced seizure and PTZ-induced kindling were used to investigate both anticonvulsive and antiepileptogenic properties of the selected azolylchromanones including 7-chloro-3-(1H-imidazol-1-yl)chroman-4-one (I), 3-(1H-1,2,4-triazol-1-yl)chroman-4-one (II), trans-3-(1H-imidazol-1-yl)-2-methylchroman-4-one (III) and trans-7-chloro-3-(1H-imidazol-1-yl)-2-methylchroman-4-one (IV). Although compounds I and II were highly effective at the dose of 5 mg/kg against acute PTZ-induced convulsions as previously reported by us, these compounds exhibited limited effects in PTZ-induced kindling model. However, compound I was found to exert respectable action in delaying seizures and reducing seizure index at the dose of 10 mg/kg. In contrast, all tested compounds showed an anticonvulsant effect due to the considerably delayed onset of seizures in lithium-pilocarpine model. Compound I exhibited more effective action in delaying seizures as well as decreasing seizure duration in this model of epilepsy. In conclusion, the azolylchromanones I-IV, especially 7-chloro-3-(1H-imidazol-1-yl)chroman-4-one (I), were effective against lithium-pilocarpine induced status epilepticus, suggesting the potential application of the test compounds in the treatment of status epilepticus.