AMPA Receptor Antagonists for the Treatment of CNS Disorders: Antiepileptics and Beyond

The α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system (CNS). Given the abundant expression and functional significance of these receptors, disruption of AMPA receptor-mediated activity has been implicated in the pathophysiology of a variety of CNS disorders. Although such disorders may represent putative therapeutic targets for AMPA receptor antagonists, pharmacological limitations have, historically, hampered the development of AMPA receptor antagonists and few, therefore, have reached clinical trials. One AMPA receptor antagonist which has successfully completed clinical development is the antiepileptic drug perampanel, identified from a focused research effort that used high-throughput screening procedures combined with structure-activity analyses to optimise lead compounds. Perampanel has a favourable pharmacokinetic profile and broad-spectrum anticonvulsant activity in several animal models, as well as consistent efficacy for the treatment of refractory partial-onset seizures in three Phase III registration studies. As a result, perampanel is the first antiepileptic drug approved in Europe, the USA, Canada, Switzerland and more than 30 other countries, to inhibit excitation of postsynaptic membranes through the selective inhibition of AMPA receptors. Here, we explore the contribution of AMPA receptors to the pathophysiology of CNS disorders, and use the discovery and development of perampanel as an example of an effective strategy to target AMPA receptors to address an unmet clinical need. Looking to the future, we also consider potential applications of AMPA receptor antagonists beyond the field of epilepsy.

Keywords: AMPA, AMPA receptor, antiepileptic drug, epilepsy, perampanel, seizures.