Strategies for identifying and developing new anticonvulsant drugs.

Abstract

The identification of new anticonvulsant drugs depends on the use of different animal models of epilepsy. The models should be mechanism-independent, able to screen a large number of compounds, at limited cost and technical expertise. Primary screening models include genetic or reflex models of epilepsy and electrically and chemically induced seizures. Once active compounds have been identified, more advanced mechanistic and seizure-specific models are needed to refine the choice of a lead compound. These can be either in vivo or in vitro models. Models known to interact with specific receptors or the production of the putative neurotransmitters of neural excitability or inhibition are valuable in assessing possible mechanisms of action. In vitro models have evolved as important tools in correlating changes in electrical phenomena and therapeutic spectrum. The use of the hippocampal slice and the cultured neuron permits classification of anticonvulsant activity based on cellular actions of the drug. Interactions by the experimental drugs with specific subcellular fractions of the central nervous system augment information on possible mechanisms of action. The final choice of compounds for development requires synthesizing and comparing all of the pharmacodynamic information with the pharmacokinetic and toxicologic data. In the final analysis, no single animal model of epilepsy known today can assure the development of better drugs for all treatment of the epilepsies.