AMPA RECEPTOR AGONISTS, ANTAGONISTS AND MODULATORS - THEIR POTENTIAL FOR CLINICAL UTILITY

Ligands with four pharmacologically distinct actions at the AMPA recep tor are discussed. The four classes of compounds include agonists, ant agonists, positive allosteric modulators, and negative allosteric modu lators of AMPA receptor function. To date, no partial agonists have be en discovered. Agonists and positive allosteric modulators may have th erapeutic potential in disease states where hypoactivity of glutamater gic tone exists. From our understanding of neuronal circuitry and its involvement in brain function, agonists and positive allosteric modula tors are predicted to improve the negative symptomatology in schizophr enia, and to improve memory, behavioural and cog nition skills in deme ntias associated with neurodegenerative disorders or trauma. Issues re lated to the structural overlap of competitive AMPA receptor antagonis ts 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 con sistently demonstrated efficacy as neuroprotective agents in models of stroke, heart attack, and brain injury. Agents from the two classes o f antagonist have been selected for clinical development, and some hav e 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 inve stigated in clinical trials.