Characterization of functional interactions of imidazoquinoxaline derivatives with benzodiazepine-gamma-aminobutyric acidA receptors
U-78875 [imidazo[1,5-a]quinoxalin-4(5H)-one, 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)] belongs to a series of imidazoquinoxaline derivatives, recently discovered ligands with high affinity for benzodiazepine receptors. In this study, we have examined the drug and its analogs for thei...
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| Veröffentlicht in: | Molecular pharmacology 1992-08, Vol.42 (2), p.294-301 |
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| creator | PETKE, J. D IM, H. K WHA BIN IM BLAKEMAN, D. P PREGENZER, J. F JACOBSEN, E. J HAMILTON, B. J CARTER, D. B |
| description | U-78875 [imidazo[1,5-a]quinoxalin-4(5H)-one, 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)] belongs to a series
of imidazoquinoxaline derivatives, recently discovered ligands with high affinity for benzodiazepine receptors. In this study,
we have examined the drug and its analogs for their modes of interaction with the receptors, with a particular emphasis on
finding molecular determinants for their functional properties. Changes in the substituents on N5 and C6 of the heterocyclic
ring produced no major effects on binding characteristics but yielded drugs of widely varying efficacy (antagonist to full
agonist), measured as gamma-aminobutyric acid (GABA)-mediated 36Cl- uptake and t-butylbicyclophosphoro[35S]thionate binding
in rat cerebrocortical membranes. The relative binding affinity and efficacy of the analogs measured in brain membranes were
similar to those in cloned GABAA receptors of the alpha 1 beta 2 gamma 2 (type I) and alpha 3 beta 2 gamma 2 (type II) subtypes.
The imidazoquinoxalines showed no marked subtype selectivity. Their Ki value against [3H]flunitrazepam binding for type I
was only 2-3 times lower than that for type II, and their rank order for agonistic activity was the same in the two subtypes,
measured as GABA-mediated Cl- currents in human kidney cells (A293) expressing the subtypes of GABAA receptors. According
to computational modeling of the drugs using both molecular and quantum mechanics, the agonistic activity of the imidazoquinoxaline
derivatives depends on the presence of a bulky alkyl substituent at N5 and the deformation of the substituted portion of the
otherwise planar ring system induced by a bulky moiety at N5 or C6. With a fixed N5 substituent (isopropyl), the relative
efficacy in the brain membranes, as well as in the cloned receptors, appeared to be dependent on the degree of the ring deformation.
This out-of-plane portion of the imidazoquinoxalines can be assigned to the general region occupied by the 5-phenyl group
of diazepam and other agonistic functional groups of several nonbenzodiazepine ligands. It seems that this region, apparently
common to various agonistic ligands, interacts with an agonistic pocket in type I and type II subtypes of the benzodiazepine
receptors in the brain. Our results also provide direct support for the view that the agonists and nonagonists share largely
overlapping binding regions in the benzodiazepine receptor, which has been proposed earlier from in vivo efficacy measure |
| format | Article |
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of imidazoquinoxaline derivatives, recently discovered ligands with high affinity for benzodiazepine receptors. In this study,
we have examined the drug and its analogs for their modes of interaction with the receptors, with a particular emphasis on
finding molecular determinants for their functional properties. Changes in the substituents on N5 and C6 of the heterocyclic
ring produced no major effects on binding characteristics but yielded drugs of widely varying efficacy (antagonist to full
agonist), measured as gamma-aminobutyric acid (GABA)-mediated 36Cl- uptake and t-butylbicyclophosphoro[35S]thionate binding
in rat cerebrocortical membranes. The relative binding affinity and efficacy of the analogs measured in brain membranes were
similar to those in cloned GABAA receptors of the alpha 1 beta 2 gamma 2 (type I) and alpha 3 beta 2 gamma 2 (type II) subtypes.
The imidazoquinoxalines showed no marked subtype selectivity. Their Ki value against [3H]flunitrazepam binding for type I
was only 2-3 times lower than that for type II, and their rank order for agonistic activity was the same in the two subtypes,
measured as GABA-mediated Cl- currents in human kidney cells (A293) expressing the subtypes of GABAA receptors. According
to computational modeling of the drugs using both molecular and quantum mechanics, the agonistic activity of the imidazoquinoxaline
derivatives depends on the presence of a bulky alkyl substituent at N5 and the deformation of the substituted portion of the
otherwise planar ring system induced by a bulky moiety at N5 or C6. With a fixed N5 substituent (isopropyl), the relative
efficacy in the brain membranes, as well as in the cloned receptors, appeared to be dependent on the degree of the ring deformation.
This out-of-plane portion of the imidazoquinoxalines can be assigned to the general region occupied by the 5-phenyl group
of diazepam and other agonistic functional groups of several nonbenzodiazepine ligands. It seems that this region, apparently
common to various agonistic ligands, interacts with an agonistic pocket in type I and type II subtypes of the benzodiazepine
receptors in the brain. Our results also provide direct support for the view that the agonists and nonagonists share largely
overlapping binding regions in the benzodiazepine receptor, which has been proposed earlier from in vivo efficacy measurements
of other series of ligands.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 1355261</identifier><identifier>CODEN: MOPMA3</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Animals ; Anti-Anxiety Agents - pharmacology ; Binding, Competitive ; Biological and medical sciences ; Bridged Bicyclo Compounds - metabolism ; Bridged Bicyclo Compounds, Heterocyclic ; Cerebral Cortex - metabolism ; Chloride Channels ; Chlorides - pharmacokinetics ; Chlorine ; Cloning, Molecular ; Drug Interactions ; Electrophysiology ; Flunitrazepam - metabolism ; GABA-A Receptor Antagonists ; Kinetics ; Male ; Medical sciences ; Membrane Proteins - drug effects ; Membrane Proteins - physiology ; Models, Chemical ; Molecular Conformation ; Neuropharmacology ; Oxadiazoles - metabolism ; Oxadiazoles - pharmacology ; Pharmacology. Drug treatments ; Psycholeptics: tranquillizer, neuroleptic ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Quinoxalines - metabolism ; Quinoxalines - pharmacology ; Radioisotopes ; Rats ; Rats, Inbred Strains ; Receptors, GABA-A - drug effects ; Receptors, GABA-A - physiology ; Structure-Activity Relationship ; Synaptosomes - metabolism ; Tritium</subject><ispartof>Molecular pharmacology, 1992-08, Vol.42 (2), p.294-301</ispartof><rights>1993 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&idt=4399667$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1355261$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PETKE, J. D</creatorcontrib><creatorcontrib>IM, H. K</creatorcontrib><creatorcontrib>WHA BIN IM</creatorcontrib><creatorcontrib>BLAKEMAN, D. P</creatorcontrib><creatorcontrib>PREGENZER, J. F</creatorcontrib><creatorcontrib>JACOBSEN, E. J</creatorcontrib><creatorcontrib>HAMILTON, B. J</creatorcontrib><creatorcontrib>CARTER, D. B</creatorcontrib><title>Characterization of functional interactions of imidazoquinoxaline derivatives with benzodiazepine-gamma-aminobutyric acidA receptors</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>U-78875 [imidazo[1,5-a]quinoxalin-4(5H)-one, 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)] belongs to a series
of imidazoquinoxaline derivatives, recently discovered ligands with high affinity for benzodiazepine receptors. In this study,
we have examined the drug and its analogs for their modes of interaction with the receptors, with a particular emphasis on
finding molecular determinants for their functional properties. Changes in the substituents on N5 and C6 of the heterocyclic
ring produced no major effects on binding characteristics but yielded drugs of widely varying efficacy (antagonist to full
agonist), measured as gamma-aminobutyric acid (GABA)-mediated 36Cl- uptake and t-butylbicyclophosphoro[35S]thionate binding
in rat cerebrocortical membranes. The relative binding affinity and efficacy of the analogs measured in brain membranes were
similar to those in cloned GABAA receptors of the alpha 1 beta 2 gamma 2 (type I) and alpha 3 beta 2 gamma 2 (type II) subtypes.
The imidazoquinoxalines showed no marked subtype selectivity. Their Ki value against [3H]flunitrazepam binding for type I
was only 2-3 times lower than that for type II, and their rank order for agonistic activity was the same in the two subtypes,
measured as GABA-mediated Cl- currents in human kidney cells (A293) expressing the subtypes of GABAA receptors. According
to computational modeling of the drugs using both molecular and quantum mechanics, the agonistic activity of the imidazoquinoxaline
derivatives depends on the presence of a bulky alkyl substituent at N5 and the deformation of the substituted portion of the
otherwise planar ring system induced by a bulky moiety at N5 or C6. With a fixed N5 substituent (isopropyl), the relative
efficacy in the brain membranes, as well as in the cloned receptors, appeared to be dependent on the degree of the ring deformation.
This out-of-plane portion of the imidazoquinoxalines can be assigned to the general region occupied by the 5-phenyl group
of diazepam and other agonistic functional groups of several nonbenzodiazepine ligands. It seems that this region, apparently
common to various agonistic ligands, interacts with an agonistic pocket in type I and type II subtypes of the benzodiazepine
receptors in the brain. Our results also provide direct support for the view that the agonists and nonagonists share largely
overlapping binding regions in the benzodiazepine receptor, which has been proposed earlier from in vivo efficacy measurements
of other series of ligands.</description><subject>Animals</subject><subject>Anti-Anxiety Agents - pharmacology</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Bridged Bicyclo Compounds - metabolism</subject><subject>Bridged Bicyclo Compounds, Heterocyclic</subject><subject>Cerebral Cortex - metabolism</subject><subject>Chloride Channels</subject><subject>Chlorides - pharmacokinetics</subject><subject>Chlorine</subject><subject>Cloning, Molecular</subject><subject>Drug Interactions</subject><subject>Electrophysiology</subject><subject>Flunitrazepam - metabolism</subject><subject>GABA-A Receptor Antagonists</subject><subject>Kinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins - drug effects</subject><subject>Membrane Proteins - physiology</subject><subject>Models, Chemical</subject><subject>Molecular Conformation</subject><subject>Neuropharmacology</subject><subject>Oxadiazoles - metabolism</subject><subject>Oxadiazoles - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Psycholeptics: tranquillizer, neuroleptic</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Quinoxalines - metabolism</subject><subject>Quinoxalines - pharmacology</subject><subject>Radioisotopes</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Receptors, GABA-A - drug effects</subject><subject>Receptors, GABA-A - physiology</subject><subject>Structure-Activity Relationship</subject><subject>Synaptosomes - metabolism</subject><subject>Tritium</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>eNo9kE1Lw0AQhhdRaq3-BGEPegxkv_JxLMUvKHhR8BYmu5tmJcnG3aS1OfvD3doic5gZnuedw5yhORGURDEh5BzN45gmUZaLj0t05f1nHBMusniGZoQJQRMyRz-rGhzIQTszwWBsh22Fq7GThxkabLqA4G_zB2Rao2CyX6Pp7Dc0ptNYhew2ZLfa450ZalzqbrLKwKT7wKMNtC1E0IZEOQ57ZyQGadQSOy11P1jnr9FFBY3XN6e-QO-PD2-r52j9-vSyWq6jmiZiiPJMCsE4TRUDJhmtqCKizJTOuNCVZimRFSE80bxUuS4lI5ISRtOYlZpwDmyBbo93-7FstSp6Z1pw--L0jcDvThy8hKZy0Enj_zXO8jxJ0qDdH7XabOqdcbrowxNbkLaxm6DRIlTO2S9FwnsM</recordid><startdate>19920801</startdate><enddate>19920801</enddate><creator>PETKE, J. D</creator><creator>IM, H. K</creator><creator>WHA BIN IM</creator><creator>BLAKEMAN, D. P</creator><creator>PREGENZER, J. F</creator><creator>JACOBSEN, E. J</creator><creator>HAMILTON, B. J</creator><creator>CARTER, D. B</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>19920801</creationdate><title>Characterization of functional interactions of imidazoquinoxaline derivatives with benzodiazepine-gamma-aminobutyric acidA receptors</title><author>PETKE, J. D ; IM, H. K ; WHA BIN IM ; BLAKEMAN, D. P ; PREGENZER, J. F ; JACOBSEN, E. J ; HAMILTON, B. J ; CARTER, D. B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h265t-98c553427d3a3c32f2d15b8de845efe371cf1146e4bd9ebc31c2132703be144a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Animals</topic><topic>Anti-Anxiety Agents - pharmacology</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Bridged Bicyclo Compounds - metabolism</topic><topic>Bridged Bicyclo Compounds, Heterocyclic</topic><topic>Cerebral Cortex - metabolism</topic><topic>Chloride Channels</topic><topic>Chlorides - pharmacokinetics</topic><topic>Chlorine</topic><topic>Cloning, Molecular</topic><topic>Drug Interactions</topic><topic>Electrophysiology</topic><topic>Flunitrazepam - metabolism</topic><topic>GABA-A Receptor Antagonists</topic><topic>Kinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins - drug effects</topic><topic>Membrane Proteins - physiology</topic><topic>Models, Chemical</topic><topic>Molecular Conformation</topic><topic>Neuropharmacology</topic><topic>Oxadiazoles - metabolism</topic><topic>Oxadiazoles - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Psycholeptics: tranquillizer, neuroleptic</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Quinoxalines - metabolism</topic><topic>Quinoxalines - pharmacology</topic><topic>Radioisotopes</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Receptors, GABA-A - drug effects</topic><topic>Receptors, GABA-A - physiology</topic><topic>Structure-Activity Relationship</topic><topic>Synaptosomes - metabolism</topic><topic>Tritium</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PETKE, J. D</creatorcontrib><creatorcontrib>IM, H. K</creatorcontrib><creatorcontrib>WHA BIN IM</creatorcontrib><creatorcontrib>BLAKEMAN, D. P</creatorcontrib><creatorcontrib>PREGENZER, J. F</creatorcontrib><creatorcontrib>JACOBSEN, E. J</creatorcontrib><creatorcontrib>HAMILTON, B. J</creatorcontrib><creatorcontrib>CARTER, D. B</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>PETKE, J. D</au><au>IM, H. K</au><au>WHA BIN IM</au><au>BLAKEMAN, D. P</au><au>PREGENZER, J. F</au><au>JACOBSEN, E. J</au><au>HAMILTON, B. J</au><au>CARTER, D. B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of functional interactions of imidazoquinoxaline derivatives with benzodiazepine-gamma-aminobutyric acidA receptors</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1992-08-01</date><risdate>1992</risdate><volume>42</volume><issue>2</issue><spage>294</spage><epage>301</epage><pages>294-301</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><coden>MOPMA3</coden><abstract>U-78875 [imidazo[1,5-a]quinoxalin-4(5H)-one, 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)] belongs to a series
of imidazoquinoxaline derivatives, recently discovered ligands with high affinity for benzodiazepine receptors. In this study,
we have examined the drug and its analogs for their modes of interaction with the receptors, with a particular emphasis on
finding molecular determinants for their functional properties. Changes in the substituents on N5 and C6 of the heterocyclic
ring produced no major effects on binding characteristics but yielded drugs of widely varying efficacy (antagonist to full
agonist), measured as gamma-aminobutyric acid (GABA)-mediated 36Cl- uptake and t-butylbicyclophosphoro[35S]thionate binding
in rat cerebrocortical membranes. The relative binding affinity and efficacy of the analogs measured in brain membranes were
similar to those in cloned GABAA receptors of the alpha 1 beta 2 gamma 2 (type I) and alpha 3 beta 2 gamma 2 (type II) subtypes.
The imidazoquinoxalines showed no marked subtype selectivity. Their Ki value against [3H]flunitrazepam binding for type I
was only 2-3 times lower than that for type II, and their rank order for agonistic activity was the same in the two subtypes,
measured as GABA-mediated Cl- currents in human kidney cells (A293) expressing the subtypes of GABAA receptors. According
to computational modeling of the drugs using both molecular and quantum mechanics, the agonistic activity of the imidazoquinoxaline
derivatives depends on the presence of a bulky alkyl substituent at N5 and the deformation of the substituted portion of the
otherwise planar ring system induced by a bulky moiety at N5 or C6. With a fixed N5 substituent (isopropyl), the relative
efficacy in the brain membranes, as well as in the cloned receptors, appeared to be dependent on the degree of the ring deformation.
This out-of-plane portion of the imidazoquinoxalines can be assigned to the general region occupied by the 5-phenyl group
of diazepam and other agonistic functional groups of several nonbenzodiazepine ligands. It seems that this region, apparently
common to various agonistic ligands, interacts with an agonistic pocket in type I and type II subtypes of the benzodiazepine
receptors in the brain. Our results also provide direct support for the view that the agonists and nonagonists share largely
overlapping binding regions in the benzodiazepine receptor, which has been proposed earlier from in vivo efficacy measurements
of other series of ligands.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>1355261</pmid><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0026-895X |
| ispartof | Molecular pharmacology, 1992-08, Vol.42 (2), p.294-301 |
| issn | 0026-895X 1521-0111 |
| language | eng |
| recordid | cdi_pubmed_primary_1355261 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Anti-Anxiety Agents - pharmacology Binding, Competitive Biological and medical sciences Bridged Bicyclo Compounds - metabolism Bridged Bicyclo Compounds, Heterocyclic Cerebral Cortex - metabolism Chloride Channels Chlorides - pharmacokinetics Chlorine Cloning, Molecular Drug Interactions Electrophysiology Flunitrazepam - metabolism GABA-A Receptor Antagonists Kinetics Male Medical sciences Membrane Proteins - drug effects Membrane Proteins - physiology Models, Chemical Molecular Conformation Neuropharmacology Oxadiazoles - metabolism Oxadiazoles - pharmacology Pharmacology. Drug treatments Psycholeptics: tranquillizer, neuroleptic Psychology. Psychoanalysis. Psychiatry Psychopharmacology Quinoxalines - metabolism Quinoxalines - pharmacology Radioisotopes Rats Rats, Inbred Strains Receptors, GABA-A - drug effects Receptors, GABA-A - physiology Structure-Activity Relationship Synaptosomes - metabolism Tritium |
| title | Characterization of functional interactions of imidazoquinoxaline derivatives with benzodiazepine-gamma-aminobutyric acidA receptors |
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