Epilepsy is a chronic
neurological disorder that is associated with various types of recurrent
seizures, which are drug-resistant in about one third of patients. Moreover,
anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including
chronic pain. Here, we investigated the
anticonvulsant activity of six new hybrid compounds based on the
pyrrolidine-2,5-dione scaffold in the 6 Hz corneal stimulation test with 44 mA stimulus intensity in mice, which is the model of pharmacoresistant
seizures. We demonstrated that two molecules, DK-10 (11) and DK-14 (14) show higher
anticonvulsant activity and similar safety profile in comparison with
valproic acid and much higher in comparison with
levetiracetam in the aforementioned test. The second aim of this study was to examine
analgesic activity of these compounds. For this purpose, the hot plate test, the
formalin test, and the
oxaliplatin-induced
peripheral neuropathy model were performed. Among tested agents DK-11 (12) revealed prominent antinociceptive activity at non-
sedative doses in the second (inflammatory) phase of the
formalin test, which is the model of tonic
pain and antiallodynic activity in the
oxaliplatin-induced
neuropathic pain, the model of painful
chemotherapy-induced
peripheral neuropathy. No cytotoxic effect on
hepatoma cells was observed. Compound DK-10 (11) had high affinity for
voltage-gated sodium channels, whereas compound DK-11 (12) showed weak binding toward
sodium and
calcium voltage-gated channels and the
NMDA receptor. As a result, hybrid compounds reported herein seem to be very promising broad spectrum
anticonvulsant molecules with collateral
analgesic activity.