Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors
This study presents the synthesis of novel substituted 4-hydroxybutanamides and their influence on the activity of murine GABA transport proteins GAT1–GAT4. The active compounds, derivatives of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide, are characterized by pIC50 values in r...
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| Veröffentlicht in: | European journal of medicinal chemistry 2011-01, Vol.46 (1), p.183-190 |
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| container_title | European journal of medicinal chemistry |
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| creator | Kulig, Katarzyna Więckowski, Krzysztof Więckowska, Anna Gajda, Justyna Pochwat, Bartłomiej Höfner, Georg C. Wanner, Klaus T. Malawska, Barbara |
| description | This study presents the synthesis of novel substituted 4-hydroxybutanamides and their influence on the activity of murine GABA transport proteins GAT1–GAT4. The active compounds, derivatives of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide, are characterized by pIC50 values in range of 3.92–5.06 and by slight subtype-selectivity. Among them N-4-chlorobenzylamide was the most potent GAT inhibitor (mGAT3), while N-benzylamide was the most active in GAT1-binding assay (pKi = 4.96). The results pointed out that benzhydryl and benzylamide moieties are crucial for the activity of this class of compounds as murine GAT inhibitors.
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► Synthesis of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide. ► Activity of murine GABA transport proteins GAT1-GAT4. ► The most active inhibitor with pKi = 4.96 in GAT1-binding assay. |
| doi_str_mv | 10.1016/j.ejmech.2010.11.001 |
| format | Article |
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[Display omitted]
► Synthesis of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide. ► Activity of murine GABA transport proteins GAT1-GAT4. ► The most active inhibitor with pKi = 4.96 in GAT1-binding assay.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2010.11.001</identifier><identifier>PMID: 21111516</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Anticonvulsants - chemical synthesis ; Anticonvulsants - chemistry ; Anticonvulsants - pharmacology ; Biological Transport - drug effects ; Butanamides ; Butanols - chemical synthesis ; Butanols - chemistry ; Butanols - pharmacology ; Drug Evaluation, Preclinical ; GABA Plasma Membrane Transport Proteins - metabolism ; GABA Uptake Inhibitors - chemical synthesis ; GABA Uptake Inhibitors - chemistry ; GABA Uptake Inhibitors - pharmacology ; GABA-uptake inhibitors ; gamma-Aminobutyric Acid - metabolism ; GAT1–4 ; Inhibitory Concentration 50 ; Mice</subject><ispartof>European journal of medicinal chemistry, 2011-01, Vol.46 (1), p.183-190</ispartof><rights>2010 Elsevier Masson SAS</rights><rights>Copyright © 2010 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c361t-27fefefe605abed428b6568297b0855c272d109ec9624a05e15b1dc72d000e593</citedby><cites>FETCH-LOGICAL-c361t-27fefefe605abed428b6568297b0855c272d109ec9624a05e15b1dc72d000e593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2010.11.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21111516$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kulig, Katarzyna</creatorcontrib><creatorcontrib>Więckowski, Krzysztof</creatorcontrib><creatorcontrib>Więckowska, Anna</creatorcontrib><creatorcontrib>Gajda, Justyna</creatorcontrib><creatorcontrib>Pochwat, Bartłomiej</creatorcontrib><creatorcontrib>Höfner, Georg C.</creatorcontrib><creatorcontrib>Wanner, Klaus T.</creatorcontrib><creatorcontrib>Malawska, Barbara</creatorcontrib><title>Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>This study presents the synthesis of novel substituted 4-hydroxybutanamides and their influence on the activity of murine GABA transport proteins GAT1–GAT4. The active compounds, derivatives of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide, are characterized by pIC50 values in range of 3.92–5.06 and by slight subtype-selectivity. Among them N-4-chlorobenzylamide was the most potent GAT inhibitor (mGAT3), while N-benzylamide was the most active in GAT1-binding assay (pKi = 4.96). The results pointed out that benzhydryl and benzylamide moieties are crucial for the activity of this class of compounds as murine GAT inhibitors.
[Display omitted]
► Synthesis of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide. ► Activity of murine GABA transport proteins GAT1-GAT4. ► The most active inhibitor with pKi = 4.96 in GAT1-binding assay.</description><subject>Animals</subject><subject>Anticonvulsants - chemical synthesis</subject><subject>Anticonvulsants - chemistry</subject><subject>Anticonvulsants - pharmacology</subject><subject>Biological Transport - drug effects</subject><subject>Butanamides</subject><subject>Butanols - chemical synthesis</subject><subject>Butanols - chemistry</subject><subject>Butanols - pharmacology</subject><subject>Drug Evaluation, Preclinical</subject><subject>GABA Plasma Membrane Transport Proteins - metabolism</subject><subject>GABA Uptake Inhibitors - chemical synthesis</subject><subject>GABA Uptake Inhibitors - chemistry</subject><subject>GABA Uptake Inhibitors - pharmacology</subject><subject>GABA-uptake inhibitors</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>GAT1–4</subject><subject>Inhibitory Concentration 50</subject><subject>Mice</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2P0zAQhi0EYrsL_wAh3ziljJ3YSS5IZQW7SCtxAM6WP6bUJYmL7QT673HUhSOeg6VXz8xoHkJeMdgyYPLtcYvHEe1hy2GN2BaAPSEb1squqrlonpINcF5XgtfNFblO6QgAQgI8J1eclSeY3JDly3nKB0w-UT05anwYwndv9UBx0cOssw8TDXs64S_qMPqlJAumNeJVmk3KPs8ZHW2qw9nF8Pts5qwnPXpXKJ3o3e79js6nrH8g9dPBG59DTC_Is70eEr58_G_It48fvt7eVw-f7z7d7h4qW0uWK97ucS0JQht0De-MFLLjfWugE8LyljsGPdpe8kaDQCYMc7ak5VYUfX1D3lzmnmL4OWPKavTJ4jDoCcOcVMeh7XmZVcjmQtoYUoq4V6foRx3PioFahaujughXq3DFmCrCS9vrxwWzGdH9a_pruADvLgCWMxePUSXrcbLofESblQv-_xv-AAtVlLY</recordid><startdate>201101</startdate><enddate>201101</enddate><creator>Kulig, Katarzyna</creator><creator>Więckowski, Krzysztof</creator><creator>Więckowska, Anna</creator><creator>Gajda, Justyna</creator><creator>Pochwat, Bartłomiej</creator><creator>Höfner, Georg C.</creator><creator>Wanner, Klaus T.</creator><creator>Malawska, Barbara</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></search><sort><creationdate>201101</creationdate><title>Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors</title><author>Kulig, Katarzyna ; Więckowski, Krzysztof ; Więckowska, Anna ; Gajda, Justyna ; Pochwat, Bartłomiej ; Höfner, Georg C. ; Wanner, Klaus T. ; Malawska, Barbara</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c361t-27fefefe605abed428b6568297b0855c272d109ec9624a05e15b1dc72d000e593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Anticonvulsants - chemical synthesis</topic><topic>Anticonvulsants - chemistry</topic><topic>Anticonvulsants - pharmacology</topic><topic>Biological Transport - drug effects</topic><topic>Butanamides</topic><topic>Butanols - chemical synthesis</topic><topic>Butanols - chemistry</topic><topic>Butanols - pharmacology</topic><topic>Drug Evaluation, Preclinical</topic><topic>GABA Plasma Membrane Transport Proteins - metabolism</topic><topic>GABA Uptake Inhibitors - chemical synthesis</topic><topic>GABA Uptake Inhibitors - chemistry</topic><topic>GABA Uptake Inhibitors - pharmacology</topic><topic>GABA-uptake inhibitors</topic><topic>gamma-Aminobutyric Acid - metabolism</topic><topic>GAT1–4</topic><topic>Inhibitory Concentration 50</topic><topic>Mice</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kulig, Katarzyna</creatorcontrib><creatorcontrib>Więckowski, Krzysztof</creatorcontrib><creatorcontrib>Więckowska, Anna</creatorcontrib><creatorcontrib>Gajda, Justyna</creatorcontrib><creatorcontrib>Pochwat, Bartłomiej</creatorcontrib><creatorcontrib>Höfner, Georg C.</creatorcontrib><creatorcontrib>Wanner, Klaus T.</creatorcontrib><creatorcontrib>Malawska, Barbara</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>Kulig, Katarzyna</au><au>Więckowski, Krzysztof</au><au>Więckowska, Anna</au><au>Gajda, Justyna</au><au>Pochwat, Bartłomiej</au><au>Höfner, Georg C.</au><au>Wanner, Klaus T.</au><au>Malawska, Barbara</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2011-01</date><risdate>2011</risdate><volume>46</volume><issue>1</issue><spage>183</spage><epage>190</epage><pages>183-190</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>This study presents the synthesis of novel substituted 4-hydroxybutanamides and their influence on the activity of murine GABA transport proteins GAT1–GAT4. The active compounds, derivatives of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide, are characterized by pIC50 values in range of 3.92–5.06 and by slight subtype-selectivity. Among them N-4-chlorobenzylamide was the most potent GAT inhibitor (mGAT3), while N-benzylamide was the most active in GAT1-binding assay (pKi = 4.96). The results pointed out that benzhydryl and benzylamide moieties are crucial for the activity of this class of compounds as murine GAT inhibitors.
[Display omitted]
► Synthesis of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide. ► Activity of murine GABA transport proteins GAT1-GAT4. ► The most active inhibitor with pKi = 4.96 in GAT1-binding assay.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>21111516</pmid><doi>10.1016/j.ejmech.2010.11.001</doi><tpages>8</tpages></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2011-01, Vol.46 (1), p.183-190 |
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| subjects | Animals Anticonvulsants - chemical synthesis Anticonvulsants - chemistry Anticonvulsants - pharmacology Biological Transport - drug effects Butanamides Butanols - chemical synthesis Butanols - chemistry Butanols - pharmacology Drug Evaluation, Preclinical GABA Plasma Membrane Transport Proteins - metabolism GABA Uptake Inhibitors - chemical synthesis GABA Uptake Inhibitors - chemistry GABA Uptake Inhibitors - pharmacology GABA-uptake inhibitors gamma-Aminobutyric Acid - metabolism GAT1–4 Inhibitory Concentration 50 Mice |
| title | Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors |
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