The identification of the pharmacophore of the triazoline anticonvulsants led to the discovery of the sigma-selective aminoalkylpyridines (AAPs), as potent orally active anticonvulsant agents, far superior to the triazolines; they are highly effective in the rat MES seizure test, with long duration of action and no apparent signs of drug-induced motor toxicity when orally administered. The AAPs have no affinity for the PCP receptor and seem to act by impairing glutamate release; thus the toxic side effects of NMDA antagonists are absent in the AAPs. NMDA receptor overstimulation by excessive glutamate release occurs during epileptic seizures, and is implicated in epileptogenesis and epilepsy. Thus NMDA/glutamate antagonists will provide prophylaxis and seizure protection, but currently no safe, orally effective NMDA/glutamate antagonists exist. Our long-term objectives are thus to develop from among the anticonvulsant AAPs, therapeutically useful antiepileptic drugs by rational analogue synthesis of active AAP leads, using 3 basic structural modifications. Variations of the heterocyclic unit and the alkyl chain, during Phase-I, have led to 6 active leads. The objectives of Phase-II are to study 4 different structural variations on the terminal amino group of the 6 AAP leads, and to prepare the R and S enantiomers of the two most active AAP racemates and determine enantiomeric specificity and activity. The most promising AAP analogue/ enantiomer emerging from these studies will be subjected to 30- and 90-day toxicity studies in the rat and the dog, to advance this compound to the IND status in early Phase-Ill. The nontoxic orally effective glutamate antagonists, developed from AAPs, have good commercial potential as clinically useful antiepileptic drugs, and also as neuroprotective agents in other neurological disorders such as stroke and Parkinson's disease where excessive glutamate levels are suspected.
Aminoalkylpyridines are safer, orally effective, sigma-selective antiepileptic agents and seem to act by impairing glutamate release. They show no affinity for PCP receptors and lack the undesirable toxic side effects of NMDA antagonists. Thus they have good potential for commercial application as clinically useful antiepileptic drugs, and also as neuroprotective agents in other neurological disorders such as stroke and Parkinson's disease, where excessive glutamate levels are implicated.
| Lin, Z; Kadaba, P K (1997) Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents. Med Res Rev 17:537-72 |
