Abstracts

Rationale: Defined as “failure of a patient’s seizures to respond to at least two antiepileptic drugs (AEDs) that are appropriately chosen and used for an adequate period to achieve sustained seizure freedom,” drug resistant epilepsy (DRE) is becoming more of an increasing burden in the epilepsy community. As a result, there is a need for researchers to develop novel therapeutics to help in the management of DRE. A previously synthesized lead KRS-5-Me-OCF3, was shown to be active in rodent seizure model and elicited its anticonvulsant effects by acting as a positive allosteric modulator of GABA at the BDZ site. The goals of our research group are three-fold (1) to conduct structure activity relationship studies that will lead to the development of a library of mono- and di-substituted fluorinated enaminone benzamides, (2) to evaluate their anticonvulsant activity for DRE in seizure animal models, and (3) to determine the plausible mechanism of action. Methods: The enaminone intermediate is synthesized via a condensation reaction involving a Michael addition and aldol condensation. The fluorinated enaminones are then synthesized by a one pot, two step acylation reaction achieving the desired products in quantifiable yield. All synthesized compounds are confirmed and characterized using HNMR, GCMS and elemental analysis methods. The in vivo animal studies are done through a collaboration with the National Institute of Neurological Disorders and Stroke – Epilepsy Therapy Screening Program (NINDS-ETSP). The purified compounds are sent to ETSP where they are evaluated in a battery of seizure animal models including the 6Hz 44mA animal model of drug resistant epilepsy. Compounds with seizure suppressing activities are sent for target screening at National Institute of Mental Health – Psychoactive Drug Screening Program (NIMH – PDSP) to be analyzed in various antiepileptic drug targets such as the GABAA receptor and the ionotropic channels.  Results: Out of the 14 compounds in our library of 2 leads compounds THA 40 and THA 36 have favorable antiseizure activities in the 6Hz 32mA and 44mA animal models. THA 40 possessed outstanding 6Hz 44mA seizure suppressing abilities with early onset and long duration of action by protecting at least 50% of the animals as early as 15 minutes and lasting through 2 hours. At 30 minutes and 1 hour 100% of the animals are protected from the electrical induced seizures. THA 36 on the other hand possessed similar pharmacological profile as levetiracetam, an AED prescribed as an add-on for DRE which lacked antiseizure activity in all seizure animal models except the 6Hz model. The active compounds were analyzed in functional binding assays and were shown to be non – inhibitors of the GABAA and BZP site receptors which is positive data for potential antiseizure agents. Conclusions: In conclusion, the tested compounds have shown antiseizure abilities in animal models of drug resistant epilepsy. We have also shown that the compounds have a probable mechanism of action by acting on the GABAA receptors in a non-inhibitory manner. Funding: N/A