Structure-function studies on N-oxalyl-diamino-dicarboxylic acids and excitatory amino acid receptors: evidence that beta-L-ODAP is a selective non-NMDA agonist.
Excitatory amino acids and their receptors play an important role in both normal synaptic transmission and excitotoxic-mediated neuronal death. In the present investigation we have prepared a series of glutamate analogs and examined the pharmacological specificity with which they interact with excitatory amino acid receptors. Included within this group of compounds is a potent excitotoxic amino acid, beta-N-oxalyl-L-alpha, beta-diaminopropionic acid (beta-L-ODAP). This excitotoxin is of particular interest because it has been identified as a major causative agent of human neurolathyrism, a disease characterized by permanent spastic paralysis. The site of action of beta-L-ODAP was delineated with both electrophysiological recordings in hippocampal slices and radioligand binding assays in synaptic plasma membranes. We report that beta-L-ODAP is a potent agonist at the non-N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. beta-L-ODAP interacts most potently with the quisqualate class of non-NMDA receptors (IC50 = 1.3 microM), less potently with the kainate receptor (IC50 = 17 microM), and very weakly with NMDA receptors. The specificity of this binding was consistent with physiological experiments that demonstrated that beta-L-ODAP-induced depolarizations were potently blocked by the newly identified non-NMDA receptor antagonist, CNQX, but were not affected by the NMDA antagonist D-AP5. These results extend recent studies that have focused on the contribution of NMDA receptors to excitotoxicity and highlight the potential involvement of non-NMDA receptors in excitotoxic-mediated cell death.
Bridges
R J
RJ
Department of Neurology, University of California, Irvine 92717.
Stevens
D R
DR
Kahle
J S
JS
Nunn
P B
PB
Kadri
M
M
Cotman
C W
CW
D000599:Amino Acids, Diamino / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism; D008297:Male; D010069:Oxadiazoles / Q000378:metabolism; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D000599:Amino Acids, Diamino; D010069:Oxadiazoles; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; C100126:oxalyldiaminopropionic acid; D007051:Ibotenic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016318:Quisqualic Acid; D007608:Kainic Acid