Quinoxaline derivatives: structure-activity relationships and physiological implications of inhibition of N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated currents and synaptic potentials
The inhibitory potencies at excitatory amino acid (EAA) receptors of 11 quinoxaline derivatives were evaluated in two-electrode voltage-clamp recordings of Xenopus oocytes injected with rat cortex mRNA. Currents activated by kainate or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (...
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Veröffentlicht in: | Molecular pharmacology 1992-02, Vol.41 (2), p.337-345 |
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Zusammenfassung: | The inhibitory potencies at excitatory amino acid (EAA) receptors of 11 quinoxaline derivatives were evaluated in two-electrode
voltage-clamp recordings of Xenopus oocytes injected with rat cortex mRNA. Currents activated by kainate or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic
acid (AMPA) in Xenopus oocytes were inhibited competitively by all the quinoxaline derivatives, with apparent Ki values ranging
from 0.27 to 300 microM against kainate and from 0.25 to 137 microM against AMPA. An excellent correlation was observed between
inhibitory potencies of the quinoxaline derivatives against kainate and AMPA currents, in support of the contention that in
this preparation these two agonists act at a single site. All 11 quinoxaline derivatives also inhibited current activated
by the combination of glycine and N-methyl-D-aspartate (NMDA), apparently acting at the glycine site, and did so over a narrower
range of apparent Ki values (0.37-8.1 microM). The correlation between the quinoxalines' kainate/AMPA potencies and their
glycine/NMDA potencies was relatively weak. Thus, the quinoxaline derivatives were all good antagonists of glycine/NMDA currents
and displayed a greater range of potencies against kainate and AMPA. The inhibitory effects of the six quinoxaline derivatives
most potent in the Xenopus oocyte experiments were also tested against the excitatory postsynaptic field potential (EPSFP)
recorded in the pyramidal cell dendritic field of the CA1 region of hippocampal slices after stimulation of the Schaffer collateral-commissural
pathways. In slices superfused with "normal" medium (containing 1 mM Mg2+), in which the EPSFP is mediated primarily by non-NMDA
receptors, IC50 values correlated closely with the Ki values against kainate/AMPA obtained in oocyte experiments but were
approximately 8-fold higher. Similarly, in slices superfused with nominally Mg(2+)-free medium, in which the EPSFP is amplified
due to a relief of the Mg2+ block of NMDA receptors, IC50 values correlated closely with the Ki values against glycine/NMDA
obtained in oocyte experiments but were 60-fold higher. This comparison of results from the two experimental systems lends
further support to the argument that hippocampal synaptic transmission is mediated postsynaptically by kainate/AMPA-type and
NMDA/glycine-type EAA receptors that are pharmacologically indistinguishable from those expressed in mRNA-injected Xenopus
oocytes. Furthermore, it suggests that EAA receptors in |
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ISSN: | 0026-895X 1521-0111 |