PHENOBARBITAL: THE CENTENARY
How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?
Article first published online: 3 DEC 2012
Wiley Periodicals, Inc. © 2012 International League Against Epilepsy
Special Issue: Phenobarbital: The Centenary - 10th European Congress on Epileptology, London - October 1, 2012
Volume 53, Issue Supplement s8, pages 3–11, December 2012
How to Cite
Bialer, M. (2012), How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?. Epilepsia, 53: 3–11. doi: 10.1111/epi.12024
- Issue published online: 3 DEC 2012
- Article first published online: 3 DEC 2012
- Antiepileptic drugs;
- Chemical properties;
- Second-generation antiepileptic drugs;
- Structure activity relationship;
- Antiepileptic drug discovery
Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative-hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.