Molecular tools for GABA A receptors: High affinity ligands for β1-containing subtypes
γ-Aminobutyric acid type A (GABA ) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3. The existence of this wide variety of subunits as well as their diverse assembly into differe...
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| Veröffentlicht in: | Scientific reports 2017-07, Vol.7 (1), p.5674 |
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| creator | Simeone, Xenia Siebert, David C B Bampali, Konstantina Varagic, Zdravko Treven, Marco Rehman, Sabah Pyszkowski, Jakob Holzinger, Raphael Steudle, Friederike Scholze, Petra Mihovilovic, Marko D Schnürch, Michael Ernst, Margot |
| description | γ-Aminobutyric acid type A (GABA
) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently, a novel binding site at extracellular α+/β- interfaces was described as the site of modulatory action of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of compounds with pronounced β1-selectivity that mainly lacks α-subunit selectivity. It constitutes the most potent β1-selective positive allosteric modulatory ligand with known binding site. In addition, a proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular tools for the detection of β1-containing receptor subtypes and the investigation of their abundance and distribution. |
| doi_str_mv | 10.1038/s41598-017-05757-4 |
| format | Article |
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) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently, a novel binding site at extracellular α+/β- interfaces was described as the site of modulatory action of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of compounds with pronounced β1-selectivity that mainly lacks α-subunit selectivity. It constitutes the most potent β1-selective positive allosteric modulatory ligand with known binding site. In addition, a proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular tools for the detection of β1-containing receptor subtypes and the investigation of their abundance and distribution.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>DNA, Complementary</subject><subject>Female</subject><subject>Ligands</subject><subject>Oocytes</subject><subject>Patch-Clamp Techniques</subject><subject>Quinolones - pharmacology</subject><subject>Rats</subject><subject>Receptors, GABA-A - drug effects</subject><subject>Receptors, GABA-A - metabolism</subject><subject>RNA, Messenger</subject><subject>Xenopus laevis</subject><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjj9uwjAcRi0kRCLKBRjQ7wIG27EVp1ta8WdhQ-qITHBSV04c2c6Qa_UgPVMj0c58yxveGz6E1pRsKcnkLnAqCokJzTERucgxn6GUES4wyxhL0CqELzJNsILTYoESJnNGpOQp-jg7q6vBKg_RORugdh6O5VsJJXhd6T46H17hZJpPUHVtOhNHsKZR3f3R_nxTXLkuqkl1DYThFsdehxc0r5UNevXHJdoc9pf3E-6HW6vv196bVvnx-v8kexr8AsE0RRE</recordid><startdate>20170718</startdate><enddate>20170718</enddate><creator>Simeone, Xenia</creator><creator>Siebert, David C B</creator><creator>Bampali, Konstantina</creator><creator>Varagic, Zdravko</creator><creator>Treven, Marco</creator><creator>Rehman, Sabah</creator><creator>Pyszkowski, Jakob</creator><creator>Holzinger, Raphael</creator><creator>Steudle, Friederike</creator><creator>Scholze, Petra</creator><creator>Mihovilovic, Marko D</creator><creator>Schnürch, Michael</creator><creator>Ernst, Margot</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-9809-2649</orcidid><orcidid>https://orcid.org/0000-0003-4984-6034</orcidid></search><sort><creationdate>20170718</creationdate><title>Molecular tools for GABA A receptors: High affinity ligands for β1-containing subtypes</title><author>Simeone, Xenia ; Siebert, David C B ; Bampali, Konstantina ; Varagic, Zdravko ; Treven, Marco ; Rehman, Sabah ; Pyszkowski, Jakob ; Holzinger, Raphael ; Steudle, Friederike ; Scholze, Petra ; Mihovilovic, Marko D ; Schnürch, Michael ; Ernst, Margot</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_287208843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>DNA, Complementary</topic><topic>Female</topic><topic>Ligands</topic><topic>Oocytes</topic><topic>Patch-Clamp Techniques</topic><topic>Quinolones - pharmacology</topic><topic>Rats</topic><topic>Receptors, GABA-A - drug effects</topic><topic>Receptors, GABA-A - metabolism</topic><topic>RNA, Messenger</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Simeone, Xenia</creatorcontrib><creatorcontrib>Siebert, David C B</creatorcontrib><creatorcontrib>Bampali, Konstantina</creatorcontrib><creatorcontrib>Varagic, Zdravko</creatorcontrib><creatorcontrib>Treven, Marco</creatorcontrib><creatorcontrib>Rehman, Sabah</creatorcontrib><creatorcontrib>Pyszkowski, Jakob</creatorcontrib><creatorcontrib>Holzinger, Raphael</creatorcontrib><creatorcontrib>Steudle, Friederike</creatorcontrib><creatorcontrib>Scholze, Petra</creatorcontrib><creatorcontrib>Mihovilovic, Marko D</creatorcontrib><creatorcontrib>Schnürch, Michael</creatorcontrib><creatorcontrib>Ernst, Margot</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Simeone, Xenia</au><au>Siebert, David C B</au><au>Bampali, Konstantina</au><au>Varagic, Zdravko</au><au>Treven, Marco</au><au>Rehman, Sabah</au><au>Pyszkowski, Jakob</au><au>Holzinger, Raphael</au><au>Steudle, Friederike</au><au>Scholze, Petra</au><au>Mihovilovic, Marko D</au><au>Schnürch, Michael</au><au>Ernst, Margot</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular tools for GABA A receptors: High affinity ligands for β1-containing subtypes</atitle><jtitle>Scientific reports</jtitle><addtitle>Sci Rep</addtitle><date>2017-07-18</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>5674</spage><pages>5674-</pages><eissn>2045-2322</eissn><abstract>γ-Aminobutyric acid type A (GABA
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| ispartof | Scientific reports, 2017-07, Vol.7 (1), p.5674 |
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| source | MEDLINE; Nature Free; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry; Springer Nature OA Free Journals |
| subjects | Animals Binding Sites DNA, Complementary Female Ligands Oocytes Patch-Clamp Techniques Quinolones - pharmacology Rats Receptors, GABA-A - drug effects Receptors, GABA-A - metabolism RNA, Messenger Xenopus laevis |
| title | Molecular tools for GABA A receptors: High affinity ligands for β1-containing subtypes |
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