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
Hauptverfasser: RANDLE, J. C. R, GUET, T, BOBICHON, C, MOREAU, C, CURUTCHET, P, LAMBOLEZ, B, DE CARVALHO, L. P, CORDI, A, LEPAGNOL, J. M
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container_issue 2
container_start_page 337
container_title Molecular pharmacology
container_volume 41
creator RANDLE, J. C. R
GUET, T
BOBICHON, C
MOREAU, C
CURUTCHET, P
LAMBOLEZ, B
DE CARVALHO, L. P
CORDI, A
LEPAGNOL, J. M
description 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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C. R ; GUET, T ; BOBICHON, C ; MOREAU, C ; CURUTCHET, P ; LAMBOLEZ, B ; DE CARVALHO, L. P ; CORDI, A ; LEPAGNOL, J. M</creator><creatorcontrib>RANDLE, J. C. R ; GUET, T ; BOBICHON, C ; MOREAU, C ; CURUTCHET, P ; LAMBOLEZ, B ; DE CARVALHO, L. P ; CORDI, A ; LEPAGNOL, J. M</creatorcontrib><description>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 situ may be nearly saturated by high local concentrations of the endogenous ligands, a condition that would contribute substantially to the apparent non-NMDA receptor selectivity of certain quinoxaline derivatives.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 1371583</identifier><identifier>CODEN: MOPMA3</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject><![CDATA[alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ; Animals ; Biological and medical sciences ; Cells, Cultured ; Cerebral Cortex - physiology ; Electrophysiology ; Evoked Potentials - drug effects ; Female ; Glycine - pharmacology ; Hippocampus - anatomy & histology ; Hippocampus - drug effects ; Hippocampus - physiology ; Ibotenic Acid - analogs & derivatives ; Ibotenic Acid - antagonists & inhibitors ; Ibotenic Acid - pharmacology ; Kainic Acid - antagonists & inhibitors ; Kainic Acid - pharmacology ; Male ; Medical sciences ; Membrane Potentials - drug effects ; Miscellaneous ; N-Methylaspartate - antagonists & inhibitors ; N-Methylaspartate - pharmacology ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Oocytes - drug effects ; Oocytes - physiology ; Oocytes - ultrastructure ; Pharmacology. Drug treatments ; Quinoxalines - pharmacology ; Rats ; Rats, Inbred Strains ; Receptors, Amino Acid ; Receptors, Cell Surface - antagonists & inhibitors ; Receptors, Cell Surface - genetics ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; RNA, Messenger - genetics ; Structure-Activity Relationship ; Synapses - drug effects ; Synapses - physiology ; Synapses - ultrastructure ; Xenopus]]></subject><ispartof>Molecular pharmacology, 1992-02, Vol.41 (2), p.337-345</ispartof><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=5117785$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1371583$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RANDLE, J. C. R</creatorcontrib><creatorcontrib>GUET, T</creatorcontrib><creatorcontrib>BOBICHON, C</creatorcontrib><creatorcontrib>MOREAU, C</creatorcontrib><creatorcontrib>CURUTCHET, P</creatorcontrib><creatorcontrib>LAMBOLEZ, B</creatorcontrib><creatorcontrib>DE CARVALHO, L. P</creatorcontrib><creatorcontrib>CORDI, A</creatorcontrib><creatorcontrib>LEPAGNOL, J. M</creatorcontrib><title>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</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>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 situ may be nearly saturated by high local concentrations of the endogenous ligands, a condition that would contribute substantially to the apparent non-NMDA receptor selectivity of certain quinoxaline derivatives.</description><subject>alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Cerebral Cortex - physiology</subject><subject>Electrophysiology</subject><subject>Evoked Potentials - drug effects</subject><subject>Female</subject><subject>Glycine - pharmacology</subject><subject>Hippocampus - anatomy &amp; histology</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - physiology</subject><subject>Ibotenic Acid - analogs &amp; derivatives</subject><subject>Ibotenic Acid - antagonists &amp; inhibitors</subject><subject>Ibotenic Acid - pharmacology</subject><subject>Kainic Acid - antagonists &amp; inhibitors</subject><subject>Kainic Acid - pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Potentials - drug effects</subject><subject>Miscellaneous</subject><subject>N-Methylaspartate - antagonists &amp; inhibitors</subject><subject>N-Methylaspartate - pharmacology</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Oocytes - drug effects</subject><subject>Oocytes - physiology</subject><subject>Oocytes - ultrastructure</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinoxalines - pharmacology</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Receptors, Amino Acid</subject><subject>Receptors, Cell Surface - antagonists &amp; inhibitors</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists &amp; inhibitors</subject><subject>RNA, Messenger - genetics</subject><subject>Structure-Activity Relationship</subject><subject>Synapses - drug effects</subject><subject>Synapses - physiology</subject><subject>Synapses - ultrastructure</subject><subject>Xenopus</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2LFDEQhhtR1nH1Jwg5qLdAks5HtzdZP2FRBAVvTU06vV3Sk8Qkvdp_0t9kZmfwJHiq1Ps8VEjqXrPjSnDKOOf3mx1jQtOuV98eNo9y_s4Yl6pjF80Fbw1XXbtrfn9e0YdfsKB3ZHQJb6HgrcsvSS5ptWVNjoKtEZaNJLdUGnyeMWYCfiRx3jKGJdyghYXgIS71cKeQMBH0M-7x2B67j_Tgyrwt9DWFHCEVKO5uiA-e_hMmZ10sIVU2Yg1GYteUnC-ny_PmIRa0JIZSQ4QlP24eTLW4J-d62Xx9--bL1Xt6_endh6tX13QWvS507DowWhrLtZlaBx0oJVvOlba9G0dhpr2SkrVKCyNH7kBKAc7WuHN9L3V72bw4zY0p_FhdLsMBs3XLAt6FNQ9GdIJpzv4rci2YUppX8elZXPf1uUNMeIC0DedNVf7szCHXv54SeIv5r6Y4N6ZTVXt-0ma8mX9ickOcIR3AHpe0DZIPYmhb0_4BYLuw5g</recordid><startdate>19920201</startdate><enddate>19920201</enddate><creator>RANDLE, J. 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R</creatorcontrib><creatorcontrib>GUET, T</creatorcontrib><creatorcontrib>BOBICHON, C</creatorcontrib><creatorcontrib>MOREAU, C</creatorcontrib><creatorcontrib>CURUTCHET, P</creatorcontrib><creatorcontrib>LAMBOLEZ, B</creatorcontrib><creatorcontrib>DE CARVALHO, L. P</creatorcontrib><creatorcontrib>CORDI, A</creatorcontrib><creatorcontrib>LEPAGNOL, J. M</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>RANDLE, J. C. R</au><au>GUET, T</au><au>BOBICHON, C</au><au>MOREAU, C</au><au>CURUTCHET, P</au><au>LAMBOLEZ, B</au><au>DE CARVALHO, L. P</au><au>CORDI, A</au><au>LEPAGNOL, J. M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1992-02-01</date><risdate>1992</risdate><volume>41</volume><issue>2</issue><spage>337</spage><epage>345</epage><pages>337-345</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><coden>MOPMA3</coden><abstract>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 situ may be nearly saturated by high local concentrations of the endogenous ligands, a condition that would contribute substantially to the apparent non-NMDA receptor selectivity of certain quinoxaline derivatives.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>1371583</pmid><tpages>9</tpages></addata></record>
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ispartof Molecular pharmacology, 1992-02, Vol.41 (2), p.337-345
issn 0026-895X
1521-0111
language eng
recordid cdi_proquest_miscellaneous_72820610
source MEDLINE; EZB-FREE-00999 freely available EZB journals
subjects alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Animals
Biological and medical sciences
Cells, Cultured
Cerebral Cortex - physiology
Electrophysiology
Evoked Potentials - drug effects
Female
Glycine - pharmacology
Hippocampus - anatomy & histology
Hippocampus - drug effects
Hippocampus - physiology
Ibotenic Acid - analogs & derivatives
Ibotenic Acid - antagonists & inhibitors
Ibotenic Acid - pharmacology
Kainic Acid - antagonists & inhibitors
Kainic Acid - pharmacology
Male
Medical sciences
Membrane Potentials - drug effects
Miscellaneous
N-Methylaspartate - antagonists & inhibitors
N-Methylaspartate - pharmacology
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oocytes - drug effects
Oocytes - physiology
Oocytes - ultrastructure
Pharmacology. Drug treatments
Quinoxalines - pharmacology
Rats
Rats, Inbred Strains
Receptors, Amino Acid
Receptors, Cell Surface - antagonists & inhibitors
Receptors, Cell Surface - genetics
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
RNA, Messenger - genetics
Structure-Activity Relationship
Synapses - drug effects
Synapses - physiology
Synapses - ultrastructure
Xenopus
title 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
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