Excitatory amino acid neurotransmission.
In recent years great progress has been made in understanding the function of ionotropic and metabotropic glutamate receptors; their pharmacology and potential therapeutic applications. It should be stressed that there are already N-methyl-D-aspartate (NMDA) antagonists in clinical use, such as memantine, which proves the feasibility of their therapeutic potential. It seems unlikely that competitive NMDA receptor antagonists and high-affinity channel blockers will find therapeutic use due to limiting side-effects, whereas agents acting at the glycineB site, NMDA receptor subtype-selective agents and moderate-affinity channel blockers are far more promising. This is supported by the fact that there are several glycineB antagonists, NMDA moderate-affinity channel blockers and NR2B-selective agents under development. Positive and negative modulators of AMPA receptors such as the AMPAkines and 2,3-benzodiazepines also show more promise than e.g. competitive antagonists. Great progress has also been made in the field of metabotropic glutamate receptors since the discovery of novel, allosteric modulatory sites for these receptors. Selective agents acting at these transmembrane sites have been developed that are more drug-like and have a much better access to the central nervous system than their competitive counterparts. The chapter will critically review preclinical and scarce clinical experience in the development of new ionotropic and metabotropic glutamate receptor modulators according to the following scheme: rational, preclinical findings in animal models and finally clinical experience, where available.
Parsons
C G
CG
Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 München, Germany.
Danysz
W
W
Zieglgänsberger
W
W
D000818:Animals; D018846:Excitatory Amino Acids / Q000502:physiology*; D006801:Humans; D009422:Nervous System Diseases / Q000503:physiopathology; D009473:Neuronal Plasticity; D017470:Receptors, Glutamate / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
D018846:Excitatory Amino Acids; D017470:Receptors, Glutamate