In vitro pharmacology of ACEA-1021 and ACEA-1031: systemically active quinoxalinediones with high affinity and selectivity for N-methyl-D-aspartate receptor glycine sites
N-methyl-D-aspartate (NMDA) receptor antagonists show therapeutic potential as neuroprotectants, analgesics, and anticonvulsants. In this context, we used electrical recording techniques to study the in vitro pharmacology of two novel quinoxalinediones, i.e., ACEA-1021 and ACEA-1031 (5-nitro-6,7- di...
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| Veröffentlicht in: | Molecular pharmacology 1995-03, Vol.47 (3), p.568-581 |
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| creator | Woodward, R M Huettner, J E Guastella, J Keana, J F Weber, E |
| description | N-methyl-D-aspartate (NMDA) receptor antagonists show therapeutic potential as neuroprotectants, analgesics, and anticonvulsants.
In this context, we used electrical recording techniques to study the in vitro pharmacology of two novel quinoxalinediones,
i.e., ACEA-1021 and ACEA-1031 (5-nitro-6,7- dichloro- and 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione, respectively).
Assays with NMDA receptors expressed by rat brain poly(A)+ RNA in Xenopus oocytes and with NMDA receptors in cultured rat
cortical neurons indicated that ACEA-1021 and ACEA-1031 are potent competitive antagonists at NMDA receptor glycine sites.
Apparent dissociation constants (Kb values) for ACEA-1021 and ACEA-1031 ranged between 6 and 8 nM for oocyte assays and between
5 and 7 nM for neuronal assays. Cloned NMDA receptors expressed in oocytes showed up to 50-fold variation in sensitivity,
depending upon subunit composition. For example, using fixed agonist concentrations (10 microM glycine and 100 microM glutamate)
IC50 values for ACEA-1021 with four binary combinations were as follows: NMDA receptor (NR)1A/2A, 29 nM; NR1A/2B, 300 nM;
NR1A/2C, 120 nM; NR1A/2D, 1500 nM. Measurement of EC50 for glycine and calculation of Kb for the inhibitors indicated that
differences in IC50 values are due to subunit-dependent variations in glycine affinity (EC50 ranged between approximately
0.1 and 1 microM) combined with variations in affinity of the antagonists themselves (Kb of approximately 2-13 nM). In addition
to the strong antagonism of NMDA receptors, ACEA-1021 and ACEA-1031 were also moderately potent competitive inhibitors of
non-NMDA receptors activated either by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or by kainate. Antagonist
affinities were similar whether measured with receptors expressed by rat brain poly(A)+ RNA in oocytes (Kb of 1-2 microM)
or with cultured neurons (Kb of 1.5-3.3 microM). Our results suggest that the in vivo neuro-protective actions of ACEA-1021
and ACEA-1031 are predominantly due to inhibition at NMDA receptor glycine sites, although additional inhibition at non-NMDA
receptors may play an ancillary role. |
| format | Article |
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In this context, we used electrical recording techniques to study the in vitro pharmacology of two novel quinoxalinediones,
i.e., ACEA-1021 and ACEA-1031 (5-nitro-6,7- dichloro- and 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione, respectively).
Assays with NMDA receptors expressed by rat brain poly(A)+ RNA in Xenopus oocytes and with NMDA receptors in cultured rat
cortical neurons indicated that ACEA-1021 and ACEA-1031 are potent competitive antagonists at NMDA receptor glycine sites.
Apparent dissociation constants (Kb values) for ACEA-1021 and ACEA-1031 ranged between 6 and 8 nM for oocyte assays and between
5 and 7 nM for neuronal assays. Cloned NMDA receptors expressed in oocytes showed up to 50-fold variation in sensitivity,
depending upon subunit composition. For example, using fixed agonist concentrations (10 microM glycine and 100 microM glutamate)
IC50 values for ACEA-1021 with four binary combinations were as follows: NMDA receptor (NR)1A/2A, 29 nM; NR1A/2B, 300 nM;
NR1A/2C, 120 nM; NR1A/2D, 1500 nM. Measurement of EC50 for glycine and calculation of Kb for the inhibitors indicated that
differences in IC50 values are due to subunit-dependent variations in glycine affinity (EC50 ranged between approximately
0.1 and 1 microM) combined with variations in affinity of the antagonists themselves (Kb of approximately 2-13 nM). In addition
to the strong antagonism of NMDA receptors, ACEA-1021 and ACEA-1031 were also moderately potent competitive inhibitors of
non-NMDA receptors activated either by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or by kainate. Antagonist
affinities were similar whether measured with receptors expressed by rat brain poly(A)+ RNA in oocytes (Kb of 1-2 microM)
or with cultured neurons (Kb of 1.5-3.3 microM). Our results suggest that the in vivo neuro-protective actions of ACEA-1021
and ACEA-1031 are predominantly due to inhibition at NMDA receptor glycine sites, although additional inhibition at non-NMDA
receptors may play an ancillary role.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 7700254</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Animals ; Binding Sites ; Brain - drug effects ; Brain - metabolism ; Brain - physiology ; Cells, Cultured ; Cloning, Molecular ; DNA, Complementary - genetics ; Electrophysiology ; Female ; Glycine - metabolism ; Kynurenic Acid - analogs & derivatives ; Kynurenic Acid - pharmacology ; Neurons - drug effects ; Neurons - metabolism ; Neurons - physiology ; Oocytes - drug effects ; Oocytes - physiology ; Oocytes - ultrastructure ; Quinoxalines - metabolism ; Quinoxalines - pharmacology ; Rats ; Receptors, Glutamate - drug effects ; Receptors, Glutamate - genetics ; Receptors, Glutamate - metabolism ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate - genetics ; Receptors, N-Methyl-D-Aspartate - metabolism ; RNA, Complementary - genetics ; RNA, Messenger - genetics ; Transcription, Genetic ; Xenopus laevis</subject><ispartof>Molecular pharmacology, 1995-03, Vol.47 (3), p.568-581</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7700254$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Woodward, R M</creatorcontrib><creatorcontrib>Huettner, J E</creatorcontrib><creatorcontrib>Guastella, J</creatorcontrib><creatorcontrib>Keana, J F</creatorcontrib><creatorcontrib>Weber, E</creatorcontrib><title>In vitro pharmacology of ACEA-1021 and ACEA-1031: systemically active quinoxalinediones with high affinity and selectivity for N-methyl-D-aspartate receptor glycine sites</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>N-methyl-D-aspartate (NMDA) receptor antagonists show therapeutic potential as neuroprotectants, analgesics, and anticonvulsants.
In this context, we used electrical recording techniques to study the in vitro pharmacology of two novel quinoxalinediones,
i.e., ACEA-1021 and ACEA-1031 (5-nitro-6,7- dichloro- and 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione, respectively).
Assays with NMDA receptors expressed by rat brain poly(A)+ RNA in Xenopus oocytes and with NMDA receptors in cultured rat
cortical neurons indicated that ACEA-1021 and ACEA-1031 are potent competitive antagonists at NMDA receptor glycine sites.
Apparent dissociation constants (Kb values) for ACEA-1021 and ACEA-1031 ranged between 6 and 8 nM for oocyte assays and between
5 and 7 nM for neuronal assays. Cloned NMDA receptors expressed in oocytes showed up to 50-fold variation in sensitivity,
depending upon subunit composition. For example, using fixed agonist concentrations (10 microM glycine and 100 microM glutamate)
IC50 values for ACEA-1021 with four binary combinations were as follows: NMDA receptor (NR)1A/2A, 29 nM; NR1A/2B, 300 nM;
NR1A/2C, 120 nM; NR1A/2D, 1500 nM. Measurement of EC50 for glycine and calculation of Kb for the inhibitors indicated that
differences in IC50 values are due to subunit-dependent variations in glycine affinity (EC50 ranged between approximately
0.1 and 1 microM) combined with variations in affinity of the antagonists themselves (Kb of approximately 2-13 nM). In addition
to the strong antagonism of NMDA receptors, ACEA-1021 and ACEA-1031 were also moderately potent competitive inhibitors of
non-NMDA receptors activated either by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or by kainate. Antagonist
affinities were similar whether measured with receptors expressed by rat brain poly(A)+ RNA in oocytes (Kb of 1-2 microM)
or with cultured neurons (Kb of 1.5-3.3 microM). Our results suggest that the in vivo neuro-protective actions of ACEA-1021
and ACEA-1031 are predominantly due to inhibition at NMDA receptor glycine sites, although additional inhibition at non-NMDA
receptors may play an ancillary role.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain - physiology</subject><subject>Cells, Cultured</subject><subject>Cloning, Molecular</subject><subject>DNA, Complementary - genetics</subject><subject>Electrophysiology</subject><subject>Female</subject><subject>Glycine - metabolism</subject><subject>Kynurenic Acid - analogs & derivatives</subject><subject>Kynurenic Acid - pharmacology</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neurons - physiology</subject><subject>Oocytes - drug effects</subject><subject>Oocytes - physiology</subject><subject>Oocytes - ultrastructure</subject><subject>Quinoxalines - metabolism</subject><subject>Quinoxalines - pharmacology</subject><subject>Rats</subject><subject>Receptors, Glutamate - drug effects</subject><subject>Receptors, Glutamate - genetics</subject><subject>Receptors, Glutamate - metabolism</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</subject><subject>Receptors, N-Methyl-D-Aspartate - genetics</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>RNA, Complementary - genetics</subject><subject>RNA, Messenger - genetics</subject><subject>Transcription, Genetic</subject><subject>Xenopus laevis</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkM1q3DAUhU1JSSdpH6GgTbMT6McaabIbpkkbCMkmhe7MHflqrCBbjqRJ4lfqU9bTTCGry-E758A9H6oFV4JTxjk_qRaMiSU1K_X7U3WW8yNjvFaGnVanWs9I1Yvqz81Ann1JkYwdpB5sDHE3kejIenO1ppwJTmBo_yvJL0mecsHeWwhhImCLf0bytPdDfIXgB2x9HDCTF1860vldR8A5P_gy_evJGPAQOWgXE7mjPZZuCvQ7hTxCKlCQJLQ4lpnuwmTnSpJ9wfy5-uggZPxyvOfVr-urh81Penv_42azvqUdX5pCt9LiSs7fMSaNVHVbL40Bo0Ep5XRrWxCwtYa7Fp00RrjaaS7kSltXi1ahPK8u3nrHFJ_2mEvT-2wxBBgw7nOjtWCiXonZ-PVo3G97bJsx-R7S1BzHnfm3N36Y4cUnbN5v3NS6kY1aGvkXSmiFnQ</recordid><startdate>19950301</startdate><enddate>19950301</enddate><creator>Woodward, R M</creator><creator>Huettner, J E</creator><creator>Guastella, J</creator><creator>Keana, J F</creator><creator>Weber, E</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19950301</creationdate><title>In vitro pharmacology of ACEA-1021 and ACEA-1031: systemically active quinoxalinediones with high affinity and selectivity for N-methyl-D-aspartate receptor glycine sites</title><author>Woodward, R M ; Huettner, J E ; Guastella, J ; Keana, J F ; Weber, E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h168t-b3ce930250038354d4688a87a555f7dcda2abc81fdef3882f4f712397cf42d5e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Brain - physiology</topic><topic>Cells, Cultured</topic><topic>Cloning, Molecular</topic><topic>DNA, Complementary - genetics</topic><topic>Electrophysiology</topic><topic>Female</topic><topic>Glycine - metabolism</topic><topic>Kynurenic Acid - analogs & derivatives</topic><topic>Kynurenic Acid - pharmacology</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neurons - physiology</topic><topic>Oocytes - drug effects</topic><topic>Oocytes - physiology</topic><topic>Oocytes - ultrastructure</topic><topic>Quinoxalines - metabolism</topic><topic>Quinoxalines - pharmacology</topic><topic>Rats</topic><topic>Receptors, Glutamate - drug effects</topic><topic>Receptors, Glutamate - genetics</topic><topic>Receptors, Glutamate - metabolism</topic><topic>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</topic><topic>Receptors, N-Methyl-D-Aspartate - genetics</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>RNA, Complementary - genetics</topic><topic>RNA, Messenger - genetics</topic><topic>Transcription, Genetic</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Woodward, R M</creatorcontrib><creatorcontrib>Huettner, J E</creatorcontrib><creatorcontrib>Guastella, J</creatorcontrib><creatorcontrib>Keana, J F</creatorcontrib><creatorcontrib>Weber, E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Woodward, R M</au><au>Huettner, J E</au><au>Guastella, J</au><au>Keana, J F</au><au>Weber, E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro pharmacology of ACEA-1021 and ACEA-1031: systemically active quinoxalinediones with high affinity and selectivity for N-methyl-D-aspartate receptor glycine sites</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1995-03-01</date><risdate>1995</risdate><volume>47</volume><issue>3</issue><spage>568</spage><epage>581</epage><pages>568-581</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>N-methyl-D-aspartate (NMDA) receptor antagonists show therapeutic potential as neuroprotectants, analgesics, and anticonvulsants.
In this context, we used electrical recording techniques to study the in vitro pharmacology of two novel quinoxalinediones,
i.e., ACEA-1021 and ACEA-1031 (5-nitro-6,7- dichloro- and 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione, respectively).
Assays with NMDA receptors expressed by rat brain poly(A)+ RNA in Xenopus oocytes and with NMDA receptors in cultured rat
cortical neurons indicated that ACEA-1021 and ACEA-1031 are potent competitive antagonists at NMDA receptor glycine sites.
Apparent dissociation constants (Kb values) for ACEA-1021 and ACEA-1031 ranged between 6 and 8 nM for oocyte assays and between
5 and 7 nM for neuronal assays. Cloned NMDA receptors expressed in oocytes showed up to 50-fold variation in sensitivity,
depending upon subunit composition. For example, using fixed agonist concentrations (10 microM glycine and 100 microM glutamate)
IC50 values for ACEA-1021 with four binary combinations were as follows: NMDA receptor (NR)1A/2A, 29 nM; NR1A/2B, 300 nM;
NR1A/2C, 120 nM; NR1A/2D, 1500 nM. Measurement of EC50 for glycine and calculation of Kb for the inhibitors indicated that
differences in IC50 values are due to subunit-dependent variations in glycine affinity (EC50 ranged between approximately
0.1 and 1 microM) combined with variations in affinity of the antagonists themselves (Kb of approximately 2-13 nM). In addition
to the strong antagonism of NMDA receptors, ACEA-1021 and ACEA-1031 were also moderately potent competitive inhibitors of
non-NMDA receptors activated either by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or by kainate. Antagonist
affinities were similar whether measured with receptors expressed by rat brain poly(A)+ RNA in oocytes (Kb of 1-2 microM)
or with cultured neurons (Kb of 1.5-3.3 microM). Our results suggest that the in vivo neuro-protective actions of ACEA-1021
and ACEA-1031 are predominantly due to inhibition at NMDA receptor glycine sites, although additional inhibition at non-NMDA
receptors may play an ancillary role.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>7700254</pmid><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0026-895X |
| ispartof | Molecular pharmacology, 1995-03, Vol.47 (3), p.568-581 |
| issn | 0026-895X 1521-0111 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_77202492 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Binding Sites Brain - drug effects Brain - metabolism Brain - physiology Cells, Cultured Cloning, Molecular DNA, Complementary - genetics Electrophysiology Female Glycine - metabolism Kynurenic Acid - analogs & derivatives Kynurenic Acid - pharmacology Neurons - drug effects Neurons - metabolism Neurons - physiology Oocytes - drug effects Oocytes - physiology Oocytes - ultrastructure Quinoxalines - metabolism Quinoxalines - pharmacology Rats Receptors, Glutamate - drug effects Receptors, Glutamate - genetics Receptors, Glutamate - metabolism Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism RNA, Complementary - genetics RNA, Messenger - genetics Transcription, Genetic Xenopus laevis |
| title | In vitro pharmacology of ACEA-1021 and ACEA-1031: systemically active quinoxalinediones with high affinity and selectivity for N-methyl-D-aspartate receptor glycine sites |
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