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.
