Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site
Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in sever...
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| Veröffentlicht in: | European journal of medicinal chemistry 2014-08, Vol.83, p.57-73 |
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| creator | Pejović, Anka Denić, Marija S. Stevanović, Dragana Damljanović, Ivan Vukićević, Mirjana Kostova, Kalina Tavlinova-Kirilova, Maya Randjelović, Pavle Stojanović, Nikola M. Bogdanović, Goran A. Blagojević, Polina D'hooghe, Matthias Radulović, Niko S. Vukićević, Rastko D. |
| description | Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4-methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABAA-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABAA receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect.
[Display omitted]
•Design and synthesis of a library of novel GABAA benzodiazepine-binding site ligands.•Potent novel N-substituted 2-ferrocenyl-1,3-thiazolidin-4-one-based anxiolytics.•Library compounds compete with known GABAA-targeting agents in vivo.•Ligand docking demonstrated favorable interactions with the GABAA receptor complex.•Incorporation of a ferrocene core was crucial for the observed anxiolytic effect. |
| doi_str_mv | 10.1016/j.ejmech.2014.05.062 |
| format | Article |
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[Display omitted]
•Design and synthesis of a library of novel GABAA benzodiazepine-binding site ligands.•Potent novel N-substituted 2-ferrocenyl-1,3-thiazolidin-4-one-based anxiolytics.•Library compounds compete with known GABAA-targeting agents in vivo.•Ligand docking demonstrated favorable interactions with the GABAA receptor complex.•Incorporation of a ferrocene core was crucial for the observed anxiolytic effect.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.05.062</identifier><identifier>PMID: 24950490</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>2-Ferrocenyl-1,3-thiazolidin-4-ones ; Animals ; Anti-Anxiety Agents - chemistry ; Anti-Anxiety Agents - metabolism ; Anti-Anxiety Agents - pharmacology ; Anxiolytic agents ; Benzodiazepines - metabolism ; Binding Sites ; Crystallography, X-Ray ; Drug Design ; Electrochemistry ; Ferrous Compounds - chemistry ; Ferrous Compounds - metabolism ; Ferrous Compounds - pharmacology ; GABAA benzodiazepine-binding site ; GABAA receptor complex ; Ligand docking ; Male ; Mice ; Molecular Docking Simulation ; Protein Binding ; Protein Conformation ; Receptors, GABA-A - chemistry ; Receptors, GABA-A - metabolism</subject><ispartof>European journal of medicinal chemistry, 2014-08, Vol.83, p.57-73</ispartof><rights>2014 Elsevier Masson SAS</rights><rights>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3232-22048712ae790fcb7730e536d74862df130d28b3ed3e58a4190d6db8cf8ff55b3</citedby><cites>FETCH-LOGICAL-c3232-22048712ae790fcb7730e536d74862df130d28b3ed3e58a4190d6db8cf8ff55b3</cites><orcidid>0000-0003-1342-7567</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2014.05.062$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24950490$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pejović, Anka</creatorcontrib><creatorcontrib>Denić, Marija S.</creatorcontrib><creatorcontrib>Stevanović, Dragana</creatorcontrib><creatorcontrib>Damljanović, Ivan</creatorcontrib><creatorcontrib>Vukićević, Mirjana</creatorcontrib><creatorcontrib>Kostova, Kalina</creatorcontrib><creatorcontrib>Tavlinova-Kirilova, Maya</creatorcontrib><creatorcontrib>Randjelović, Pavle</creatorcontrib><creatorcontrib>Stojanović, Nikola M.</creatorcontrib><creatorcontrib>Bogdanović, Goran A.</creatorcontrib><creatorcontrib>Blagojević, Polina</creatorcontrib><creatorcontrib>D'hooghe, Matthias</creatorcontrib><creatorcontrib>Radulović, Niko S.</creatorcontrib><creatorcontrib>Vukićević, Rastko D.</creatorcontrib><title>Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4-methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABAA-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABAA receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect.
[Display omitted]
•Design and synthesis of a library of novel GABAA benzodiazepine-binding site ligands.•Potent novel N-substituted 2-ferrocenyl-1,3-thiazolidin-4-one-based anxiolytics.•Library compounds compete with known GABAA-targeting agents in vivo.•Ligand docking demonstrated favorable interactions with the GABAA receptor complex.•Incorporation of a ferrocene core was crucial for the observed anxiolytic effect.</description><subject>2-Ferrocenyl-1,3-thiazolidin-4-ones</subject><subject>Animals</subject><subject>Anti-Anxiety Agents - chemistry</subject><subject>Anti-Anxiety Agents - metabolism</subject><subject>Anti-Anxiety Agents - pharmacology</subject><subject>Anxiolytic agents</subject><subject>Benzodiazepines - metabolism</subject><subject>Binding Sites</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Electrochemistry</subject><subject>Ferrous Compounds - chemistry</subject><subject>Ferrous Compounds - metabolism</subject><subject>Ferrous Compounds - pharmacology</subject><subject>GABAA benzodiazepine-binding site</subject><subject>GABAA receptor complex</subject><subject>Ligand docking</subject><subject>Male</subject><subject>Mice</subject><subject>Molecular Docking Simulation</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Receptors, GABA-A - chemistry</subject><subject>Receptors, GABA-A - metabolism</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtvEzEUhS1ERdPCP0DISxZ4uH7NY4OUFlqQKnVT1taMfYc4mtjBdqKm2_5xJkphyepuvnOO7kfIew4VB15_Xle43qBdVQK4qkBXUItXZMGbumVSaPWaLEAIybSQ6pxc5LwGAF0DvCHnQnUaVAcL8vzVZxv3mA40jrQPjz5Oh-ItFWzElKLFcJgY_yRZWfn-KU7e-cAUiwEzxUdMxYdf9HZ5tVzShBa3JSbqQ8HU2-JjoHvf07JCOmB4im6uwK0PyAYf3DGZfcG35Gzsp4zvXu4l-Xnz7eH6O7u7v_1xvbxjVgopmBCg2oaLHpsORjs0jQTUsnaNamvhRi7BiXaQ6CTqtle8A1e7obVjO45aD_KSfDz1blP8vcNczGZ-HqepDxh32XCtOt60ndQzqk6oTTHnhKPZJr_p08FwMEf9Zm1O-s1RvwFtZv1z7MPLwm7YoPsX-ut7Br6cAJz_3HtMJluPwaLzs71iXPT_X_gDEbaZIA</recordid><startdate>20140818</startdate><enddate>20140818</enddate><creator>Pejović, Anka</creator><creator>Denić, Marija S.</creator><creator>Stevanović, Dragana</creator><creator>Damljanović, Ivan</creator><creator>Vukićević, Mirjana</creator><creator>Kostova, Kalina</creator><creator>Tavlinova-Kirilova, Maya</creator><creator>Randjelović, Pavle</creator><creator>Stojanović, Nikola M.</creator><creator>Bogdanović, Goran A.</creator><creator>Blagojević, Polina</creator><creator>D'hooghe, Matthias</creator><creator>Radulović, Niko S.</creator><creator>Vukićević, Rastko D.</creator><general>Elsevier Masson SAS</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/0000-0003-1342-7567</orcidid></search><sort><creationdate>20140818</creationdate><title>Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site</title><author>Pejović, Anka ; Denić, Marija S. ; Stevanović, Dragana ; Damljanović, Ivan ; Vukićević, Mirjana ; Kostova, Kalina ; Tavlinova-Kirilova, Maya ; Randjelović, Pavle ; Stojanović, Nikola M. ; Bogdanović, Goran A. ; Blagojević, Polina ; D'hooghe, Matthias ; Radulović, Niko S. ; Vukićević, Rastko D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3232-22048712ae790fcb7730e536d74862df130d28b3ed3e58a4190d6db8cf8ff55b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>2-Ferrocenyl-1,3-thiazolidin-4-ones</topic><topic>Animals</topic><topic>Anti-Anxiety Agents - chemistry</topic><topic>Anti-Anxiety Agents - metabolism</topic><topic>Anti-Anxiety Agents - pharmacology</topic><topic>Anxiolytic agents</topic><topic>Benzodiazepines - metabolism</topic><topic>Binding Sites</topic><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>Electrochemistry</topic><topic>Ferrous Compounds - chemistry</topic><topic>Ferrous Compounds - metabolism</topic><topic>Ferrous Compounds - pharmacology</topic><topic>GABAA benzodiazepine-binding site</topic><topic>GABAA receptor complex</topic><topic>Ligand docking</topic><topic>Male</topic><topic>Mice</topic><topic>Molecular Docking Simulation</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Receptors, GABA-A - chemistry</topic><topic>Receptors, GABA-A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pejović, Anka</creatorcontrib><creatorcontrib>Denić, Marija S.</creatorcontrib><creatorcontrib>Stevanović, Dragana</creatorcontrib><creatorcontrib>Damljanović, Ivan</creatorcontrib><creatorcontrib>Vukićević, Mirjana</creatorcontrib><creatorcontrib>Kostova, Kalina</creatorcontrib><creatorcontrib>Tavlinova-Kirilova, Maya</creatorcontrib><creatorcontrib>Randjelović, Pavle</creatorcontrib><creatorcontrib>Stojanović, Nikola M.</creatorcontrib><creatorcontrib>Bogdanović, Goran A.</creatorcontrib><creatorcontrib>Blagojević, Polina</creatorcontrib><creatorcontrib>D'hooghe, Matthias</creatorcontrib><creatorcontrib>Radulović, Niko S.</creatorcontrib><creatorcontrib>Vukićević, Rastko D.</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>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pejović, Anka</au><au>Denić, Marija S.</au><au>Stevanović, Dragana</au><au>Damljanović, Ivan</au><au>Vukićević, Mirjana</au><au>Kostova, Kalina</au><au>Tavlinova-Kirilova, Maya</au><au>Randjelović, Pavle</au><au>Stojanović, Nikola M.</au><au>Bogdanović, Goran A.</au><au>Blagojević, Polina</au><au>D'hooghe, Matthias</au><au>Radulović, Niko S.</au><au>Vukićević, Rastko D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2014-08-18</date><risdate>2014</risdate><volume>83</volume><spage>57</spage><epage>73</epage><pages>57-73</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4-methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABAA-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABAA receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect.
[Display omitted]
•Design and synthesis of a library of novel GABAA benzodiazepine-binding site ligands.•Potent novel N-substituted 2-ferrocenyl-1,3-thiazolidin-4-one-based anxiolytics.•Library compounds compete with known GABAA-targeting agents in vivo.•Ligand docking demonstrated favorable interactions with the GABAA receptor complex.•Incorporation of a ferrocene core was crucial for the observed anxiolytic effect.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>24950490</pmid><doi>10.1016/j.ejmech.2014.05.062</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-1342-7567</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 2-Ferrocenyl-1,3-thiazolidin-4-ones Animals Anti-Anxiety Agents - chemistry Anti-Anxiety Agents - metabolism Anti-Anxiety Agents - pharmacology Anxiolytic agents Benzodiazepines - metabolism Binding Sites Crystallography, X-Ray Drug Design Electrochemistry Ferrous Compounds - chemistry Ferrous Compounds - metabolism Ferrous Compounds - pharmacology GABAA benzodiazepine-binding site GABAA receptor complex Ligand docking Male Mice Molecular Docking Simulation Protein Binding Protein Conformation Receptors, GABA-A - chemistry Receptors, GABA-A - metabolism |
| title | Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site |
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