AMPA receptor agonists, antagonists and modulators: their potential for clinical utility

Ligands with four pharmacologically distinct actions at the AMPA receptor are discussed. The four classes of compounds include agonists, antagonists, positive allosteric modulators, and negative allosteric modulators of AMPA receptor function. To date, no partial agonists have been discovered. Agonists and positive allosteric modulators may have therapeutic potential in disease states where hypoactivity of glutamatergic tone exists. From our understanding of neuronal circuitry and its involvement in brain function, agonists and positive allosteric modulators are predicted to improve the negative symptomatology in schizophrenia, and to improve memory, behavioural and cognition skills in dementias associated with neurodegenerative disorders or trauma. Issues related to the structural overlap of competitive AMPA receptor antagonists and NMDA glycine site (GlyN) antagonists are addressed; emphasis is directed toward AMPA antagonist activity. Competitive antagonists and negative allosteric modulators (non-competitive antagonists) have consistently demonstrated efficacy as neuroprotective agents in models of stroke, heart attack, and brain injury. Agents from the two classes of antagonist have been selected for clinical development, and some have entered clinical trials. At least one positive allosteric modulator is in clinical trials to determine whether it can improve clinical end-points in patients with Alzheimer’s disease. No agonist has been investigated in clinical trials.