Amino Acid Neurotransmitters and New Approaches to Anticonvulsant Drug Action

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Abstract
Summary: Amino acids provide the most universal and important inhibitory (γ‐aminobutyric acid (GABA), glycine) and excitatory (glutamate, aspartate, cysteic acid, cysteine sulphinic acid) neurotransmitters in the brain. An anticonvulsant action may be produced (1) by enhancing inhibitory (GABAergic) processes, and (2) by diminishing excitatory transmission. Possible pharmacological mechanisms for enhancing GABA‐mediated inhibition include (1) GABA agonist action, (2) GABA prodrugs, (3) drugs facilitating GABA release from terminals, (4) inhibition of GABA‐transaminase, (5) allosteric enhancement of the efficacy of GABA at the receptor complex, (6) direction action on the chloride ionophore, and (7) inhibition of GABA reuptake. Examples of these approaches include the use of irreversible GABA‐transaminase inhibitors, such as γ‐vinyl GABA, and the development of anticonvulsant β‐carbolines that interact with the “benzodiazepine receptor.” Pharmacological mechanisms for diminishing excitatory transmission include (1) enzyme inhibitors that decrease the maximal rate of synthesis of glutamate or asparate, (2) drugs that decrease the synaptic release of glutamate or aspartate, and (3) drugs that block the post‐synaptic action of excitatory amino acids. Compounds that selectively antagonise excitation due to dicarboxylic amino acids have recently been developed. Those that selectively block excitation produced by N‐methyl‐D‐aspartate (and aspartate) have proved to be potent anticonvulsants in many animal models of epilepsy. This provides a novel approach to the design of anticonvulsant drugs. Summary: Animal studies show potent anticonvulsant actions of pharmacological agents that either specifically enhance GABAergic inhibition or decrease excitatory transmission by dicarboxylic amino acids. This evidence supports the concept that some established anticonvulsant drugs act on inhibitory and excitatory transmission. It provides a theoretical framework for the search for new anticonvulsant drugs. The optimal anticonvulsant agents are likely to possess a subtle combination of selective actions on both excitation and inhibition.