New Insight into the Central Benzodiazepine Receptor–Ligand Interactions: Design, Synthesis, Biological Evaluation, and Molecular Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and Related Compounds
3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K i values spanning from the low nanomolar to the submicromolar range. In p...
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| Veröffentlicht in: | Journal of medicinal chemistry 2011-08, Vol.54 (16), p.5694-5711 |
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| creator | Anzini, Maurizio Valenti, Salvatore Braile, Carlo Cappelli, Andrea Vomero, Salvatore Alcaro, Stefano Ortuso, Francesco Marinelli, Luciana Limongelli, Vittorio Novellino, Ettore Betti, Laura Giannaccini, Gino Lucacchini, Antonio Daniele, Simona Martini, Claudia Ghelardini, Carla Di Cesare Mannelli, Lorenzo Giorgi, Gianluca Mascia, Maria Paola Biggio, Giovanni |
| description | 3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of 36Cl– in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant α1β2γ2L, α2β1γ2L, and α5β2γ2L human GABAA receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer’s GABAA homology model. |
| doi_str_mv | 10.1021/jm2001597 |
| format | Article |
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Most of the compounds showed high affinity for bovine and human CBR, their K i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of 36Cl– in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant α1β2γ2L, α2β1γ2L, and α5β2γ2L human GABAA receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer’s GABAA homology model.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm2001597</identifier><identifier>PMID: 21751815</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Benzodiazepines - chemistry ; Benzodiazepines - metabolism ; Benzodiazepines - pharmacology ; Binding Sites ; Binding, Competitive - drug effects ; Cattle ; Cerebral Cortex - drug effects ; Cerebral Cortex - metabolism ; Chlorides - pharmacokinetics ; Flumazenil - metabolism ; HEK293 Cells ; Humans ; Ligands ; Male ; Mice ; Models, Molecular ; Molecular Structure ; Motor Activity - drug effects ; Protein Structure, Tertiary ; Protein Subunits - chemistry ; Protein Subunits - genetics ; Protein Subunits - metabolism ; Radioligand Assay ; Receptors, GABA-A - chemistry ; Receptors, GABA-A - genetics ; Receptors, GABA-A - metabolism ; Synaptosomes - drug effects ; Synaptosomes - metabolism ; Tritium ; Xenopus laevis</subject><ispartof>Journal of medicinal chemistry, 2011-08, Vol.54 (16), p.5694-5711</ispartof><rights>Copyright © 2011 American Chemical Society</rights><rights>2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm2001597$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm2001597$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21751815$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Anzini, Maurizio</creatorcontrib><creatorcontrib>Valenti, Salvatore</creatorcontrib><creatorcontrib>Braile, Carlo</creatorcontrib><creatorcontrib>Cappelli, Andrea</creatorcontrib><creatorcontrib>Vomero, Salvatore</creatorcontrib><creatorcontrib>Alcaro, Stefano</creatorcontrib><creatorcontrib>Ortuso, Francesco</creatorcontrib><creatorcontrib>Marinelli, Luciana</creatorcontrib><creatorcontrib>Limongelli, Vittorio</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Betti, Laura</creatorcontrib><creatorcontrib>Giannaccini, Gino</creatorcontrib><creatorcontrib>Lucacchini, Antonio</creatorcontrib><creatorcontrib>Daniele, Simona</creatorcontrib><creatorcontrib>Martini, Claudia</creatorcontrib><creatorcontrib>Ghelardini, Carla</creatorcontrib><creatorcontrib>Di Cesare Mannelli, Lorenzo</creatorcontrib><creatorcontrib>Giorgi, Gianluca</creatorcontrib><creatorcontrib>Mascia, Maria Paola</creatorcontrib><creatorcontrib>Biggio, Giovanni</creatorcontrib><title>New Insight into the Central Benzodiazepine Receptor–Ligand Interactions: Design, Synthesis, Biological Evaluation, and Molecular Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and Related Compounds</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of 36Cl– in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant α1β2γ2L, α2β1γ2L, and α5β2γ2L human GABAA receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer’s GABAA homology model.</description><subject>Animals</subject><subject>Benzodiazepines - chemistry</subject><subject>Benzodiazepines - metabolism</subject><subject>Benzodiazepines - pharmacology</subject><subject>Binding Sites</subject><subject>Binding, Competitive - drug effects</subject><subject>Cattle</subject><subject>Cerebral Cortex - drug effects</subject><subject>Cerebral Cortex - metabolism</subject><subject>Chlorides - pharmacokinetics</subject><subject>Flumazenil - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Ligands</subject><subject>Male</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Motor Activity - drug effects</subject><subject>Protein Structure, Tertiary</subject><subject>Protein Subunits - chemistry</subject><subject>Protein Subunits - genetics</subject><subject>Protein Subunits - metabolism</subject><subject>Radioligand Assay</subject><subject>Receptors, GABA-A - chemistry</subject><subject>Receptors, GABA-A - genetics</subject><subject>Receptors, GABA-A - metabolism</subject><subject>Synaptosomes - drug effects</subject><subject>Synaptosomes - metabolism</subject><subject>Tritium</subject><subject>Xenopus laevis</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctuEzEUhi0EoqGw4AWQN4hNDL7NjV0bCq0ULmphhaqRZ3ySOPLYw9gGJSvegTfsk-DQgsTqnMX3fzo6P0JPGX3JKGevtgOnlBVNdQ_NWMEpkTWV99GMUs4JL7k4Qo9C2FJKBePiITrirCpYzYoZuvkAP_CFC2a9idi46HHcAF6Ai5Oy-BTc3muj9jAaB_gSehijn25-_lqatXI6JyNMqo_Gu_Aav4HscXN8tXPZEkyY41PjrV-bPsvOviub1AGd40P2vbfQJ6umvGmwxq2xX2FBrlIXookpgsYl-bQBt7NEnhMzGK32_iubF0Rd5yGvu__uC3-0l2DVIbrww-iT0-ExerBSNsCTu3mMvrw9-7w4J8uP7y4WJ0uiWEUj0Vxxvep0UakVo5I1UPdcaVk2tBe6aXhZ8KrSJdM1A9EwrfOXVceLvAophThGL2694-S_JQixHUzowVrlwKfQ1rWUXLK6zuSzOzJ1A-h2nMygpl37t5YMPL8FVB_arU-Ty4e3jLaHutt_dYvfDs-d1A</recordid><startdate>20110825</startdate><enddate>20110825</enddate><creator>Anzini, Maurizio</creator><creator>Valenti, Salvatore</creator><creator>Braile, Carlo</creator><creator>Cappelli, Andrea</creator><creator>Vomero, Salvatore</creator><creator>Alcaro, Stefano</creator><creator>Ortuso, Francesco</creator><creator>Marinelli, Luciana</creator><creator>Limongelli, Vittorio</creator><creator>Novellino, Ettore</creator><creator>Betti, Laura</creator><creator>Giannaccini, Gino</creator><creator>Lucacchini, Antonio</creator><creator>Daniele, Simona</creator><creator>Martini, Claudia</creator><creator>Ghelardini, Carla</creator><creator>Di Cesare Mannelli, Lorenzo</creator><creator>Giorgi, Gianluca</creator><creator>Mascia, Maria Paola</creator><creator>Biggio, Giovanni</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>7X8</scope></search><sort><creationdate>20110825</creationdate><title>New Insight into the Central Benzodiazepine Receptor–Ligand Interactions: Design, Synthesis, Biological Evaluation, and Molecular Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and Related Compounds</title><author>Anzini, Maurizio ; Valenti, Salvatore ; Braile, Carlo ; Cappelli, Andrea ; Vomero, Salvatore ; Alcaro, Stefano ; Ortuso, Francesco ; Marinelli, Luciana ; Limongelli, Vittorio ; Novellino, Ettore ; Betti, Laura ; Giannaccini, Gino ; Lucacchini, Antonio ; Daniele, Simona ; Martini, Claudia ; Ghelardini, Carla ; Di Cesare Mannelli, Lorenzo ; Giorgi, Gianluca ; Mascia, Maria Paola ; Biggio, Giovanni</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a170t-d2a2dfbd57af10419e8c2ad4690c3d99265277d61d81e391dd480ab2591d34433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Benzodiazepines - chemistry</topic><topic>Benzodiazepines - metabolism</topic><topic>Benzodiazepines - pharmacology</topic><topic>Binding Sites</topic><topic>Binding, Competitive - drug effects</topic><topic>Cattle</topic><topic>Cerebral Cortex - drug effects</topic><topic>Cerebral Cortex - metabolism</topic><topic>Chlorides - pharmacokinetics</topic><topic>Flumazenil - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Ligands</topic><topic>Male</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Motor Activity - drug effects</topic><topic>Protein Structure, Tertiary</topic><topic>Protein Subunits - chemistry</topic><topic>Protein Subunits - genetics</topic><topic>Protein Subunits - metabolism</topic><topic>Radioligand Assay</topic><topic>Receptors, GABA-A - chemistry</topic><topic>Receptors, GABA-A - genetics</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Synaptosomes - drug effects</topic><topic>Synaptosomes - metabolism</topic><topic>Tritium</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Anzini, Maurizio</creatorcontrib><creatorcontrib>Valenti, Salvatore</creatorcontrib><creatorcontrib>Braile, Carlo</creatorcontrib><creatorcontrib>Cappelli, Andrea</creatorcontrib><creatorcontrib>Vomero, Salvatore</creatorcontrib><creatorcontrib>Alcaro, Stefano</creatorcontrib><creatorcontrib>Ortuso, Francesco</creatorcontrib><creatorcontrib>Marinelli, Luciana</creatorcontrib><creatorcontrib>Limongelli, Vittorio</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Betti, Laura</creatorcontrib><creatorcontrib>Giannaccini, Gino</creatorcontrib><creatorcontrib>Lucacchini, Antonio</creatorcontrib><creatorcontrib>Daniele, Simona</creatorcontrib><creatorcontrib>Martini, Claudia</creatorcontrib><creatorcontrib>Ghelardini, Carla</creatorcontrib><creatorcontrib>Di Cesare Mannelli, Lorenzo</creatorcontrib><creatorcontrib>Giorgi, Gianluca</creatorcontrib><creatorcontrib>Mascia, Maria Paola</creatorcontrib><creatorcontrib>Biggio, Giovanni</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anzini, Maurizio</au><au>Valenti, Salvatore</au><au>Braile, Carlo</au><au>Cappelli, Andrea</au><au>Vomero, Salvatore</au><au>Alcaro, Stefano</au><au>Ortuso, Francesco</au><au>Marinelli, Luciana</au><au>Limongelli, Vittorio</au><au>Novellino, Ettore</au><au>Betti, Laura</au><au>Giannaccini, Gino</au><au>Lucacchini, Antonio</au><au>Daniele, Simona</au><au>Martini, Claudia</au><au>Ghelardini, Carla</au><au>Di Cesare Mannelli, Lorenzo</au><au>Giorgi, Gianluca</au><au>Mascia, Maria Paola</au><au>Biggio, Giovanni</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New Insight into the Central Benzodiazepine Receptor–Ligand Interactions: Design, Synthesis, Biological Evaluation, and Molecular Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and Related Compounds</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2011-08-25</date><risdate>2011</risdate><volume>54</volume><issue>16</issue><spage>5694</spage><epage>5711</epage><pages>5694-5711</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of 36Cl– in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant α1β2γ2L, α2β1γ2L, and α5β2γ2L human GABAA receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer’s GABAA homology model.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21751815</pmid><doi>10.1021/jm2001597</doi><tpages>18</tpages></addata></record> |
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| subjects | Animals Benzodiazepines - chemistry Benzodiazepines - metabolism Benzodiazepines - pharmacology Binding Sites Binding, Competitive - drug effects Cattle Cerebral Cortex - drug effects Cerebral Cortex - metabolism Chlorides - pharmacokinetics Flumazenil - metabolism HEK293 Cells Humans Ligands Male Mice Models, Molecular Molecular Structure Motor Activity - drug effects Protein Structure, Tertiary Protein Subunits - chemistry Protein Subunits - genetics Protein Subunits - metabolism Radioligand Assay Receptors, GABA-A - chemistry Receptors, GABA-A - genetics Receptors, GABA-A - metabolism Synaptosomes - drug effects Synaptosomes - metabolism Tritium Xenopus laevis |
| title | New Insight into the Central Benzodiazepine Receptor–Ligand Interactions: Design, Synthesis, Biological Evaluation, and Molecular Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and Related Compounds |
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