Amino acids such as
L-glutamate und
L-aspartate are major excitatory
neurotransmitters in the mammalian central nervous system (CNS) and potential
neurotoxins (
excitotoxins), which can destroy central neurons by excessive activation of respective receptors. In the last three decades evidence has accumulated that
excitatory amino acids (EAA) are involved in many neurological diseases and that pharmacological intervention offers prospects of novel and more effective
therapies. Three different receptor types for EAA have been identified, each being named by the selective agonist to which it is preferentially sensitive, i.e.
N-methyl-D-aspartate- (
NMDA),
kainate- and
quisqualate-receptors. In this review interest is focused primarily on the
NMDA-receptor, whose structure has been subject of numerous electrophysiological and biochemical studies. Today, it is well established that the
NMDA-receptor-ionophore complex has an agonist binding site for
glutamate,
NMDA and related EAAs which is coupled with an
ion channel permeable to Na+, K+, Cl- and Ca2+. Four other binding sites for
glycine,
phencyclidine, Mg2+ and Zn2+ have been identified which can differentially modulate the function of the
NMDA receptor. An additional
polyamine binding site has recently been reported. Numerous studies on experimental animals demonstrate that modulators of
NMDA-mediated neurotransmission may have
antiepileptic,
anxiolytic, muscle-relaxant and memory-enhancing effects. Particular interest has gained the possible neuroprotective efficacy of
NMDA-receptor antagonists in neurological diseases such as
hypoxia/
ischemia,
hypoglycemia,
epilepsy and chronic
neurodegenerative disorders (Huntington's, Alzheimer's and
Parkinson's disease,
amyotrophic lateral sclerosis, and
AIDS encephalopathy).(ABSTRACT TRUNCATED AT 250 WORDS)