Pharmacology of AMPA/Kainate Receptor Ligands and Their Therapeutic Potential in Neurological and Psychiatric Disorders

It has been postulated, consistent with the ubiquitous presence of glutamatergic neurons in the brain, that defects in glutamatergic neurotransmission are associated with many human neurological and psychiatric disorders. This review evaluates the possible application of ligands acting on glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate (KA) receptors to minimise the pathology and/or symptoms of various diseases. Glutamate activation of AMPA receptors is thought to mediate most fast synaptic neurotransmission in the brain, while transmission via KA receptors contributes only a minor component. Variants of the protein subunits forming these receptors greatly extend the pharmacological and electrophysiological properties of AMPA/KA receptors. Disease and drug use can differentially affect the expression of the subunits and their variants. Ligands bind to AMPA receptors by competing with glutamate at the glutamate binding site, or non-competitively at other sites on the proteins (allosteric modulators). Ligands showing selective competitive antagonist actions at the AMPA/ KA class of glutamate receptors were first reported in 1988, and the systemically active antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX) was first shown to have useful therapeutic effects on animal models of neurological diseases in 1990. Since then, newer antagonists with increased potency, higher specificity, increased water solubility, and a longer duration of action in vivo have been developed. Negative allosteric modulators such as the prototype GYKI-52466 also block AMPA receptors but have little action at KA receptors. Positive allosteric modulators enhance glutamatergic neurotransmission at AMPA receptors. Polyamines and adamantane derivatives bind within the ion channel of calcium-permeable AMPA receptors. The latest developments include ligands selective for KA receptors containing Glu-R5 subunits. Evidence for advantages of AMPA receptor antagonists over N -methyl-D-aspartate (NMDA) receptor antagonists for symptomatic treatment of neurological and psychiatric conditions, and for minimising neuronal loss occurring after acute neurological diseases, such as physical trauma, ischaemia or status epilepticus, have been shown in animal models. However, as yet AMPA receptor antagonists have not been shown to be effective in clinical trials. On the other hand, a limited number of clinical trials have been reported for AMPA receptor ligands that enhance glutamatergic neurotransmission by extending the ion channel opening time (positive allosteric modulators). These acute studies demonstrate enhanced memory capability in both young and aged humans, without any apparent serious adverse effects. The use of these allosteric modulators as antipsychotic drugs is also possible. However, the long term use of both direct agonists and positive allosteric modulators must be approached with considerable caution because of potential adverse effects.