Evaluation of the anticonvulsant effect of novel melatonin derivatives in the intravenous pentylenetetrazol seizure test in mice

Abstract

The design of new pharmacologically active compounds with affinity to melatonin receptors has become an area of great interest during the last decade. Recently, we reported that newly synthesized melatonin derivatives, containing aroylhydrazone moiety in the indole scaffold, with the highest affinity to the elaborated pharmacophore model, possess an anticonvulsant activity in the maximal electroshock (MES) and 6Hz test in mice. We aimed further to explore the effect of these melatonin derivatives and the role of melatonin receptors on seizure threshold measured by the timed intravenous pentylenetetrazole (iv PTZ) infusion test in mice. Carbamazepine (CBZ) and melatonin were used as positive controls. Three out of six compounds, 3c, 3f, and 3e, respectively, dose-dependently increased the PTZ-induced seizure thresholds for myoclonic twitch, clonic, and tonic seizures comparable to the effect of CBZ and melatonin. The anticonvulsant effect of 3c, 3f, and 3e was blocked by the non-selective melatonin receptor antagonist luzindol suggesting the involvement of melatonin receptors in the activity of these compounds. Also docking study of 3c, 3f and 3e in the melatonin-binding site of melatonin receptor confirm the possible mechanism of action of these compounds involving melatonin receptors. Our previous and present results suggest that 3c, 3f, and 3e can be considered promising agents with anticonvulsant activity on melatonin receptors in the brain.