AMPA/Kainate Receptors

AMPA and kainate receptors belong to a common family of ionotropic glutamate receptors. Molecular biology has revealed some of the molecular features that are responsible for selective ion permeability of the receptor comp.lex. The diversity of subunits and their combination into hetero-oligomeric recep or complexes have provided evidence that several subtypes of AMPA/kainate receptors exist within the central nervous system. AMPA (2) and kainic acid (4) are agonists that have been used to define receptor pharmacology, including the issue of receptor desensitization and its relationship to excitotoxicity. Selective AMPA antagonists, such as NBQX (9), and mixed AMPA and NMDA glycine site (GlyN) antagonists, such as PNQX (11), have demonstrated significant neuroprotection in several models of cerebral ischemia and neuronal injury, and have provided the basis for extensive research into this mechanism for neuroprotection by the pharmaceutical industry. Physicochemical properties including poor aqueous solubility and high crystallinity of quinoxalinedione-based molecules have hampered their development. Pharmacophore models of the AMPA recognition site have been generated that are useful for identifying molecular features that may circumvent those issues. Alternative templates have been investigated that are hoped to retain intrinsic affinity at the glutamate recognition site of AMPA/kainate receptors comparable or superior to that of 9 and 11. Noncompetitive antagonists of AMPA receptor function may have a therapeutic advantage in that they will not be reversed by a pool of excess glutamate that is associated with neuronal injury or ischemia. Compounds based upon the 2,3- benzodiazepine analog, GYKI 52466 (28) are reported to have significant neuroprotective and anticonvulsant properties. There is evidence that positive modulation of AMPA/kainate receptors may be useful for improving memory formation·and cognitive abilities. Analogs of cyclothiazide (27) and aniracetam (31) have been investigated to delay or reverse cognitive deficits associated with neurodegenerative diseases. The molecules that are discussed herein are a first generation of agents that modulate and have helped to define AMPA/kainate receptor function. It is expected that a second generation of agents will provide clinical utility in a number of neurological disorders, and provide further insight into the functional activity of receptor subtypes.