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Therapeutic Potential of AMPA Receptor Ligands in Neurological Disorders

  • Pharmacology and Pathophysiology
  • Therapeutic Potential of AMPA Receptor Ligands
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Abstract

Summary

Neurodegeneration produced by toxic levels of glutamate is now suggested to be a causative factor in the pathologies found in a number of neurological diseases. This glutamate-induced toxicity is mainly due to activation of both the N-methyl-D-aspartate (NMDA) and non-NMDA classes of glutamate receptors. Hence, drugs that act as antagonists at these receptors are potentially neuroprotective in many diseases. Noncompetitive antagonists appear to be the preferred type of ligand because their action is not diminished by the levels of glutamate reached during a trauma. In addition, they may have reduced adverse effects compared with competitive antagonists.

The group of non-NMDA receptors consists of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate receptors, which can be defined on the basis of their pharmacology or by recombinant gene techniques. The latter methods demonstrate a far more complex picture for the receptors. Studies show the presence of at least 9 different protein subunits, which, when linked in groups of 5, comprise the AMPA and kainate subclasses of glutamate receptors.

The native non-NMDA receptor has at least 3 separate binding sites at which non-NMDA receptor antagonists can act: glutamate, desensitisation and intra-ion channel binding sites. The glutamate binding site is the site for competitive antagonists such as 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX). Non-NMDA receptors show rapid desensitisation, which limits the duration of activation of the receptor. One group of noncompetitive antagonists (e.g. GYKI 52466) binds at this desensitisation site. Another group of noncompetitive antagonists, the spider and wasp toxins, bind at the third site within the ion channel.

Protection against ischaemic damage is the most well researched indication for the application of non-NMDA receptor antagonists and the one that shows the most promise. However, almost all studies in any indication so far have only been carried out in rodents. Recent evidence suggests that antagonists at non-NMDA receptors are more effective neuroprotective agents than NMDA receptor antagonists after ischaemic attacks, and that their administration can be delayed for up to 12 hours without seriously compromising the extent of neuroprotection.

Protection against neuronal loss caused by physical injury to the brain or motor neuron disease are other potential uses for non-NMDA receptor antagonists. The antagonists are less effective than the NMDA receptor antagonists against neuronal loss caused by hypoglycaemia or status epilepticus. Non-NMDA receptor antagonists are also effective as anticonvulsants and as antiemetics during cancer chemotherapy. As antiparkinsonian drugs, they show marked synergistic effects when given in combination with levodopa, but are unlikely to be useful as a monotherapy for this disorder.

Despite evidence for potential in a number of disorders, prolonged use of non-NMDA receptor antagonists may be contraindicated due to their adverse effects on memory, cognition, motor activity and autonomic functions. Nephrotoxicity due to poor solubility and a short duration of action are also limitations of at least some of the current generation of non-NMDA receptor antagonists. Minimising these adverse effects, particularly with drugs that are selective for the receptor subunits, and translating the results of animal studies to human conditions will be awaited with interest.

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  1. Department of Psychiatry and Behavioural Science, School of Medicine, University of Auckland, Private Bag 92 019, Auckland, New Zealand

    Gordon J. Lees

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Lees, G.J. Therapeutic Potential of AMPA Receptor Ligands in Neurological Disorders. CNS Drugs 5, 51–74 (1996). https://doi.org/10.2165/00023210-199605010-00005

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