Phenylglycines can evoke quisqualate-primed depolarizations in rat cingulate cortex: an effect associated with [3H]DL-AP4 uptake.
Depolarization could be evoked in slices of rat cingulate cortex by the normally non-excitatory compound L-2-amino-4-phosphonobutyrate (L-AP4) if the slices had been sensitized by exposure to quisqualate. The magnitude of the response to L-AP4 was dependent on the concentrations of both L-AP4 and quisqualate and was inhibited by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonism. A series of phenylglycine analogues were capable of evoking similar dose-dependent depolarizations in the rat cingulate cortex following quisqualate sensitization, the most potent being (S)-4-carboxy-3-hydroxyphenylglycine. If the superfusate collected during application of (S)-4-carboxy-3-hydroxyphenylglycine to a quisqualate-sensitized slice was administered to a slice not previously exposed to quisqualate, a small depolarization was obtained. All the compounds shown to be capable of evoking the quisqualate-sensitized response showed affinity for the L-AP4 uptake site whilst having no affinity at ionotropic glutamate receptors and different profiles of activity at metabotropic glutamate receptors. None of the compounds was active at the metabotropic glutamate 4a receptor. There was a statistically significant correlation between a compound's effectiveness in inhibiting [3H]DL-AP4 uptake into rat cortical synaptosomes and its potency in evoking quisqualate-sensitized depolarization. It is concluded that this response may be the result of hetero-exchange between L-AP4 ligands and quisqualate.
Sheardown
M J
MJ
Novo Nordisk A/S, Health Care Discovery, Måløv, Denmark.
Thomsen
C
C
D000613:Aminobutyrates / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000502:physiology*; D009994:Osmolar Concentration; D010879:Piperazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology*; D051381:Rats; D014316:Tritium
D000613:Aminobutyrates; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D011810:Quinoxalines; D014316:Tritium; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C078245:4-carboxy-3-hydroxyphenylglycine; D016318:Quisqualic Acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C012729:2-amino-4-phosphonobutyric acid; D005998:Glycine