New Antiepileptic Drugs: From Serendipity to Rational Discovery
Article first published online: 5 NOV 2007
Volume 33, Issue Supplement s1, pages S1–S6, January 1992
How to Cite
Porter, R. J. and Rogawski, M. A. (1992), New Antiepileptic Drugs: From Serendipity to Rational Discovery. Epilepsia, 33: S1–S6. doi: 10.1111/j.1528-1157.1992.tb05895.x
- Issue published online: 5 NOV 2007
- Article first published online: 5 NOV 2007
- Ion channels
Summary: Antiepileptic drug discovery has made enormous progress from the serendipity and screening processes of earlier days to the rational drug development of today. The modern era of research began with the recognition that enhancement of inhibitory processes in the brain might favorably influence the propensity for seizures, γ-aminobutyric acid (GABA) being the main inhibitory transmitter. Work in this field led to the development of vigabatrin, which inhibits the enzyme responsible for the degradation of GABA. More recently, research has focused on the therapeutic potential of blocking excitatory amino acids—in particular glutamate. Of the three receptors for glutamate, the N-methyl-d-aspartate (NMDA) receptor is considered the one of most interest in epilepsy, and research on a series of competitive NMDA receptor antagonists—especially those that are orally active—is in the forefront of antiepileptic drug development today. A further alternative for diminishing neuronal excitability is to modulate sodium, potassium, or calcium channels. The latter are especially implicated in absence seizures.
Antiepileptic drug discovery has evolved from serendipity through random screening to a scientific era where drugs are designed rationally according to modern principals of neuroscience and the art of medicinal chemistry. Of the research directions currently being pursued, the following appear to be particularly promising: enhancement of inhibition, reduction in excitation, and modulation of the ionic channels that are the fundamental mediators of neuronal excitability. The application of modern approaches to drug discovery provides some optimism that effective new compounds will be marketed in the coming decade, with the promise of diminished suffering by persons with uncontrolled epilepsy.