THERAPEUTIC POTENTIAL OF AMPA RECEPTOR LIGANDS IN NEUROLOGICAL DISORDERS

Neurodegeneration produced by toxic levels of glutamate is now suggest ed to be a causative factor in the pathologies found in a number of ne urological diseases. This glutamate-induced toxicity is mainly due to activation of both the N-methyl-D-aspartate (NMDA) and non-NMDA classe s of glutamate receptors. Hence, drugs that act as antagonists at thes e receptors are potentially neuroprotective in many diseases. Noncompe titive antagonists appear to be the preferred type of ligand because t heir action is not diminished by the levels of,glutamate reached durin g a trauma. In addition, they may have reduced adverse effects compare d with competitive antagonists. The group of non-NMDA receptors consis ts of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate receptors, which can be defined on the basis of their pha rmacology or by recombinant gene techniques. The latter methods demons trate a far more complex picture for the receptors. Studies show the p resence of at least 9 different protein subunits, which, when linked i n groups of 5, comprise the AMPA and kainate subclasses of glutamate r eceptors. The native non-NMDA receptor has at least 3 separate binding sites at which non-NMDA receptor antagonists can act: glutamate desen sitisation and intra-ion channel binding sites. The glutamate binding site is the site for competitive antagonists such as dihydroxy-6-nitro -7-sulphamoyl-benzo(F)quinoxaline (NBQX). Non-NMDA receptors show rapi d desensitisation, which limits the duration of activation of the rece ptor. One group of noncompetitive antagonists (e.g. GYKI 52466) binds at this desensitisation site. Another group of noncompetitive antagoni sts, the spider and wasp toxins, bind at the third site within the ion channel. protection against ischaemic damage is the most well researc hed indication for the application of non-NMDA receptor antagonists an d the one that shows the most promise. However, almost all studies in any indication so far have only been carried out in rodents. Recent ev idence suggests that antagonists at non-NMDA receptors are more effect ive neuroprotective agents than NMDA receptor antagonists after ischae mic attacks, and that their administration can be delayed for up to 12 hours without seriously compromising the extent of neuroprotection. p rotection against neuronal loss caused by physical injury to the brain or motor neuron disease are other potential uses for non-NMDA recepto r antagonists. The antagonists are less effective than the NMDA recept or antagonists against neuronal loss caused by hypoglycaemia or status epilepticus. Non-NMDA receptor antagonists are;also effective as anti convulsants and as antiemetics during cancer chemotherapy. As antipark insonian drugs, they show marked synergistic effects when given in com bination with levodopa, but are unlikely to be useful as a monotherapy for this disorder. Despite evidence for potential in a number of diso rders, prolonged use of non-NMDA receptor antagonists may be contraind icated due to their adverse effects on memory, cognition, motor activi ty and autonomic functions. Nephrotoxicity due to poor solubility and a short duration of action are also limitations of at least some of th e current generation of non-NMDA receptor antagonists. Minimising thes e adverse effects, particularly with drugs that are selective for the receptor subunits, and translating the results of animal studies to hu man conditions will be awaited with interest.