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Molecular Pharmacology

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Abstract

Effects of (+)-HA-966 and 7-chlorokynurenic acid on the kinetics of N-methyl-D-aspartate receptor agonist responses in rat cultured cortical neurons.

J A Kemp and T Priestley
Molecular Pharmacology May 1991, 39 (5) 666-670;
J A Kemp
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Abstract

It has been suggested that one of the effects of glycine at the N-methyl-D-aspartate (NMDA) receptor complex is to reduce the amount of apparent receptor desensitization. Thus, blockade with a glycine site antagonist results in NMDA responses that show an increased amount of fade. In agreement with this, we found that antagonism of NMDA-evoked whole-cell currents by 7-chlorokynurenic acid (7-Cl-KYNA) indeed resulted in NMDA responses that displayed an increased amount of fade. However, those responses that were antagonized by (+)-HA-966 showed the opposite, i.e., less tendency to fade. On examination of these responses, it appeared that those produced in the presence of (+)-HA-966 were slower in onset and faster in offset than control responses recorded in the presence of glycine alone. Kinetic analysis of the on- and off-rates of NMDA- and glutamate-evoked NMDA receptor-mediated responses revealed that these were markedly affected by (+)-HA-966 but only slightly by 7-Cl-KYNA. The decrease of the glutamate response decay time constant and the increase of the response rise time constant produced by (+)-HA-966 indicated that it reduced the affinity of glutamate for its recognition site on the NMDA receptor by 5-fold. These results suggest that binding of (+)-HA-966 to the glycine site on the NMDA receptor complex produces an allosteric reduction in the affinity of agonists for the glutamate recognition site, whereas 7-Cl-KYNA has relatively little effect and, thus, acts more as a pure antagonist at the glycine site.

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Molecular Pharmacology
Vol. 39, Issue 5
1 May 1991
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Abstract

Effects of (+)-HA-966 and 7-chlorokynurenic acid on the kinetics of N-methyl-D-aspartate receptor agonist responses in rat cultured cortical neurons.

J A Kemp and T Priestley
Molecular Pharmacology May 1, 1991, 39 (5) 666-670;

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Abstract

Effects of (+)-HA-966 and 7-chlorokynurenic acid on the kinetics of N-methyl-D-aspartate receptor agonist responses in rat cultured cortical neurons.

J A Kemp and T Priestley
Molecular Pharmacology May 1, 1991, 39 (5) 666-670;
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