| The goal of this research project was to evaluate the anticonvulsant properties of a series of piperidinecarboxylic acid derivatives which have a basic pharmacophore resembling that of remacemide. These compounds were synthesized in the Division of Molecular Pharmacology of Northeast Louisiana University under the supervision of Dr. Michael Crider. The ability of these compounds to function as anticonvulsants was evaluated using the seizure models of maximal electroshock (MES), pentamethylenetetrazole (PTZ) and N-methyl-dl-aspartate (NMdlA) injection. Besides testing anticonvulsant properties, motor impairment and learning impairment associated with these compounds were evaluated using the rotorod apparatus and Morris Water Maze protocol. The therapeutic index (TI) was calculated using the formula TI = TD{dollar}sb{lcub}50{rcub}{dollar}/ED{dollar}sb{lcub}50{rcub}{dollar}, where TD{dollar}sb{lcub}50{rcub}{dollar} represents the toxic dose in 50% of the population, and ED{dollar}sb{lcub}50{rcub}{dollar} represents the effective dose that protects against MES in 50% of population.; Additional in vitro assays were performed to elucidate a possible mode of action of these compounds. Binding assays were carried out to calculate the binding affinities of the synthesized compounds for the PCP site on the N-Methyl-D-Aspartate (NMDA) receptor complex. Previous studies suggested that this group of compounds was capable of displacing ({dollar}sp3{dollar}H) TCP from the PCP site. Finally, the receptor expression system in xenopus oocytes was used to elucidate possible mechanisms of action of these compounds.; Considering the limited number of tests that were performed, a great deal of information has been gathered which aids in understanding the pharmacology of this series of compounds. The first piece of information obtained was that these compounds can prevent MES-induced seizures in a dose-dependent fashion. Second, it was realized that through structural modification the therapeutic indices of these compounds could be improved. Third, these compounds have no effect on seizure initiation at ED{dollar}sb{lcub}50{rcub}{dollar} dose for MES. Fourth, according to our initial hypothesis, these compounds blocked the N-methyl-dl-Aspartate-induced seizures. However, they failed to displace TCP in the binding studies. Finally, the oocyte data suggests that the mechanism of action of these compounds is not directly related to the blockade of the NMDA receptor complex. |
