The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity
The low binding affinity of the approved anxiolytic drug etifoxine (Stresam) at the steroidogenic 18 kDa translocator protein (TSPO) has questioned the specific contribution of this protein in mediating the etifoxine neurosteroidogenic efficacy. Residence time (RT) at the binding site of the classic...
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| Veröffentlicht in: | ACS chemical neuroscience 2017-07, Vol.8 (7), p.1448-1454 |
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| creator | Costa, Barbara Cavallini, Chiara Da Pozzo, Eleonora Taliani, Sabrina Da Settimo, Federico Martini, Claudia |
| description | The low binding affinity of the approved anxiolytic drug etifoxine (Stresam) at the steroidogenic 18 kDa translocator protein (TSPO) has questioned the specific contribution of this protein in mediating the etifoxine neurosteroidogenic efficacy. Residence time (RT) at the binding site of the classical TSPO ligand PK11195 is emerging as a relevant neurosteroidogenic efficacy measure rather than the binding affinity. Here etifoxine was evaluated for (i) the in vitro neurosteroidogenic activity in comparison to poorly neurosteroidogenic reference TSPO ligands (PK11195 and Ro5-4864) and (ii) the affinity and RT at [3H]PK11195 and [3H]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [3H]PK11195 site and low affinity/long RT at the [3H]Ro5-4864 site, at which etifoxine competitively bound. These findings suggest that the long RT of etifoxine at the Ro5-4864 binding site could account for its high neurosteroidogenic efficacy. |
| doi_str_mv | 10.1021/acschemneuro.7b00027 |
| format | Article |
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Residence time (RT) at the binding site of the classical TSPO ligand PK11195 is emerging as a relevant neurosteroidogenic efficacy measure rather than the binding affinity. Here etifoxine was evaluated for (i) the in vitro neurosteroidogenic activity in comparison to poorly neurosteroidogenic reference TSPO ligands (PK11195 and Ro5-4864) and (ii) the affinity and RT at [3H]PK11195 and [3H]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [3H]PK11195 site and low affinity/long RT at the [3H]Ro5-4864 site, at which etifoxine competitively bound. These findings suggest that the long RT of etifoxine at the Ro5-4864 binding site could account for its high neurosteroidogenic efficacy.</description><identifier>ISSN: 1948-7193</identifier><identifier>EISSN: 1948-7193</identifier><identifier>DOI: 10.1021/acschemneuro.7b00027</identifier><identifier>PMID: 28362078</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anti-Anxiety Agents - metabolism ; Anti-Anxiety Agents - pharmacology ; Benzodiazepinones - metabolism ; Benzodiazepinones - pharmacology ; Binding Sites ; Binding, Competitive ; Carrier Proteins - metabolism ; Cell Line, Tumor ; Flumazenil - pharmacology ; GABA Modulators - pharmacology ; Hypolipidemic Agents - pharmacology ; Isoquinolines - pharmacology ; Kidney - drug effects ; Kidney - metabolism ; Kinetics ; Neurotransmitter Agents - metabolism ; Oxazines - metabolism ; Oxazines - pharmacokinetics ; Oxazines - pharmacology ; Pregnenolone - metabolism ; Radioligand Assay ; Rats ; Receptors, GABA-A - metabolism ; Thermodynamics ; Tritium</subject><ispartof>ACS chemical neuroscience, 2017-07, Vol.8 (7), p.1448-1454</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a394t-6148c4386f7aebb65389d8049cf1a402e528261fbc43dddf84c9e83ea4491cd13</citedby><cites>FETCH-LOGICAL-a394t-6148c4386f7aebb65389d8049cf1a402e528261fbc43dddf84c9e83ea4491cd13</cites><orcidid>0000-0002-7598-1275 ; 0000-0003-4762-8949 ; 0000-0001-9379-3027</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acschemneuro.7b00027$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acschemneuro.7b00027$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28362078$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Costa, Barbara</creatorcontrib><creatorcontrib>Cavallini, Chiara</creatorcontrib><creatorcontrib>Da Pozzo, Eleonora</creatorcontrib><creatorcontrib>Taliani, Sabrina</creatorcontrib><creatorcontrib>Da Settimo, Federico</creatorcontrib><creatorcontrib>Martini, Claudia</creatorcontrib><title>The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity</title><title>ACS chemical neuroscience</title><addtitle>ACS Chem. Neurosci</addtitle><description>The low binding affinity of the approved anxiolytic drug etifoxine (Stresam) at the steroidogenic 18 kDa translocator protein (TSPO) has questioned the specific contribution of this protein in mediating the etifoxine neurosteroidogenic efficacy. Residence time (RT) at the binding site of the classical TSPO ligand PK11195 is emerging as a relevant neurosteroidogenic efficacy measure rather than the binding affinity. Here etifoxine was evaluated for (i) the in vitro neurosteroidogenic activity in comparison to poorly neurosteroidogenic reference TSPO ligands (PK11195 and Ro5-4864) and (ii) the affinity and RT at [3H]PK11195 and [3H]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [3H]PK11195 site and low affinity/long RT at the [3H]Ro5-4864 site, at which etifoxine competitively bound. These findings suggest that the long RT of etifoxine at the Ro5-4864 binding site could account for its high neurosteroidogenic efficacy.</description><subject>Animals</subject><subject>Anti-Anxiety Agents - metabolism</subject><subject>Anti-Anxiety Agents - pharmacology</subject><subject>Benzodiazepinones - metabolism</subject><subject>Benzodiazepinones - pharmacology</subject><subject>Binding Sites</subject><subject>Binding, Competitive</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Flumazenil - pharmacology</subject><subject>GABA Modulators - pharmacology</subject><subject>Hypolipidemic Agents - pharmacology</subject><subject>Isoquinolines - pharmacology</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kinetics</subject><subject>Neurotransmitter Agents - metabolism</subject><subject>Oxazines - metabolism</subject><subject>Oxazines - pharmacokinetics</subject><subject>Oxazines - pharmacology</subject><subject>Pregnenolone - metabolism</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Receptors, GABA-A - metabolism</subject><subject>Thermodynamics</subject><subject>Tritium</subject><issn>1948-7193</issn><issn>1948-7193</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kLtOwzAUhi0EouXyBgh5ZAnYiZs4Y0FAkSpAtMyRY580rhq7xA7QjUfHpQV1YjoXff-5_AidUXJJSUyvhHSyhsZA19rLrCSExNke6tOc8SijebK_k_fQkXNzQtKc8PQQ9WKepDHJeB99TWvAQ_Op7WLltcS3Xlf2UxvA19ooh73F08nzE36xg4jxlP20tZnhifaAP7Sv8diG8gWcVmAk4KluAE9q-7GmBB7pWY0f10c6D63Vys7AhEVD6fW79qsTdFCJhYPTbTxGr3e305tRNH66f7gZjiOR5MxHKWVcsoSnVSagLNNBwnPFCctlRQUjMQxiHqe0KgOklKo4kznwBARjOZWKJsfoYjN32dq3DpwvGu0kLBbCgO1cQTlPKKcDkgWUbVAZjnYtVMWy1Y1oVwUlxdr7Ytf7Yut9kJ1vN3RlA-pP9Gt2AMgGCPJibrvWhIf_n_kNrE2UIA</recordid><startdate>20170719</startdate><enddate>20170719</enddate><creator>Costa, Barbara</creator><creator>Cavallini, Chiara</creator><creator>Da Pozzo, Eleonora</creator><creator>Taliani, Sabrina</creator><creator>Da Settimo, Federico</creator><creator>Martini, Claudia</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7598-1275</orcidid><orcidid>https://orcid.org/0000-0003-4762-8949</orcidid><orcidid>https://orcid.org/0000-0001-9379-3027</orcidid></search><sort><creationdate>20170719</creationdate><title>The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity</title><author>Costa, Barbara ; Cavallini, Chiara ; Da Pozzo, Eleonora ; Taliani, Sabrina ; Da Settimo, Federico ; Martini, Claudia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a394t-6148c4386f7aebb65389d8049cf1a402e528261fbc43dddf84c9e83ea4491cd13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Anti-Anxiety Agents - metabolism</topic><topic>Anti-Anxiety Agents - pharmacology</topic><topic>Benzodiazepinones - metabolism</topic><topic>Benzodiazepinones - pharmacology</topic><topic>Binding Sites</topic><topic>Binding, Competitive</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Flumazenil - pharmacology</topic><topic>GABA Modulators - pharmacology</topic><topic>Hypolipidemic Agents - pharmacology</topic><topic>Isoquinolines - pharmacology</topic><topic>Kidney - drug effects</topic><topic>Kidney - metabolism</topic><topic>Kinetics</topic><topic>Neurotransmitter Agents - metabolism</topic><topic>Oxazines - metabolism</topic><topic>Oxazines - pharmacokinetics</topic><topic>Oxazines - pharmacology</topic><topic>Pregnenolone - metabolism</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Thermodynamics</topic><topic>Tritium</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Costa, Barbara</creatorcontrib><creatorcontrib>Cavallini, Chiara</creatorcontrib><creatorcontrib>Da Pozzo, Eleonora</creatorcontrib><creatorcontrib>Taliani, Sabrina</creatorcontrib><creatorcontrib>Da Settimo, Federico</creatorcontrib><creatorcontrib>Martini, Claudia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>ACS chemical neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Costa, Barbara</au><au>Cavallini, Chiara</au><au>Da Pozzo, Eleonora</au><au>Taliani, Sabrina</au><au>Da Settimo, Federico</au><au>Martini, Claudia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity</atitle><jtitle>ACS chemical neuroscience</jtitle><addtitle>ACS Chem. Neurosci</addtitle><date>2017-07-19</date><risdate>2017</risdate><volume>8</volume><issue>7</issue><spage>1448</spage><epage>1454</epage><pages>1448-1454</pages><issn>1948-7193</issn><eissn>1948-7193</eissn><abstract>The low binding affinity of the approved anxiolytic drug etifoxine (Stresam) at the steroidogenic 18 kDa translocator protein (TSPO) has questioned the specific contribution of this protein in mediating the etifoxine neurosteroidogenic efficacy. Residence time (RT) at the binding site of the classical TSPO ligand PK11195 is emerging as a relevant neurosteroidogenic efficacy measure rather than the binding affinity. Here etifoxine was evaluated for (i) the in vitro neurosteroidogenic activity in comparison to poorly neurosteroidogenic reference TSPO ligands (PK11195 and Ro5-4864) and (ii) the affinity and RT at [3H]PK11195 and [3H]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [3H]PK11195 site and low affinity/long RT at the [3H]Ro5-4864 site, at which etifoxine competitively bound. These findings suggest that the long RT of etifoxine at the Ro5-4864 binding site could account for its high neurosteroidogenic efficacy.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28362078</pmid><doi>10.1021/acschemneuro.7b00027</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-7598-1275</orcidid><orcidid>https://orcid.org/0000-0003-4762-8949</orcidid><orcidid>https://orcid.org/0000-0001-9379-3027</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Anti-Anxiety Agents - metabolism Anti-Anxiety Agents - pharmacology Benzodiazepinones - metabolism Benzodiazepinones - pharmacology Binding Sites Binding, Competitive Carrier Proteins - metabolism Cell Line, Tumor Flumazenil - pharmacology GABA Modulators - pharmacology Hypolipidemic Agents - pharmacology Isoquinolines - pharmacology Kidney - drug effects Kidney - metabolism Kinetics Neurotransmitter Agents - metabolism Oxazines - metabolism Oxazines - pharmacokinetics Oxazines - pharmacology Pregnenolone - metabolism Radioligand Assay Rats Receptors, GABA-A - metabolism Thermodynamics Tritium |
| title | The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity |
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