Conformationally defined neurotransmitter analogs. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer
In order to determine the conformational requirements for binding of L-glutamate to the proteins involved in the process of neurotransmission, rigid analogues containing an embedded glutamate moiety have been prepared. These "conformer mimics", the pyrrolidine-2,4-dicarboxylates 4, 7, 11,...
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| Veröffentlicht in: | Journal of medicinal chemistry 1991-02, Vol.34 (2), p.717-725 |
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| container_title | Journal of medicinal chemistry |
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| creator | Bridges, Richard J Stanley, Mark S Anderson, Michael W Cotman, Carl W Chamberlin, A. Richard |
| description | In order to determine the conformational requirements for binding of L-glutamate to the proteins involved in the process of neurotransmission, rigid analogues containing an embedded glutamate moiety have been prepared. These "conformer mimics", the pyrrolidine-2,4-dicarboxylates 4, 7, 11, and 14, were synthesized from commercially available trans-4-hydroxy-L-proline and cis-4-hydroxy-D-proline, and then were tested for their ability to inhibit the high-affinity transport of [3H]-L-glutamate into synaptosomes and to block the binding of radioligands to the NMDA (N-methyl-D-aspartate), KA (kainate), and QA (quisqualate) glutamate neurotransmitter receptor sites. While none of the four analogues binds effectively to the excitatory receptors, the L-trans-isomer 7 is a potent and selective competitive inhibitor of L-glutamate transport. These results delineate a specific structural/conformational preference for binding to the uptake system that is distinct from that required for binding to the NMDA, KA, and QA receptors. |
| doi_str_mv | 10.1021/jm00106a037 |
| format | Article |
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Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer</title><source>ACS Publications</source><source>MEDLINE</source><creator>Bridges, Richard J ; Stanley, Mark S ; Anderson, Michael W ; Cotman, Carl W ; Chamberlin, A. Richard</creator><creatorcontrib>Bridges, Richard J ; Stanley, Mark S ; Anderson, Michael W ; Cotman, Carl W ; Chamberlin, A. Richard</creatorcontrib><description>In order to determine the conformational requirements for binding of L-glutamate to the proteins involved in the process of neurotransmission, rigid analogues containing an embedded glutamate moiety have been prepared. These "conformer mimics", the pyrrolidine-2,4-dicarboxylates 4, 7, 11, and 14, were synthesized from commercially available trans-4-hydroxy-L-proline and cis-4-hydroxy-D-proline, and then were tested for their ability to inhibit the high-affinity transport of [3H]-L-glutamate into synaptosomes and to block the binding of radioligands to the NMDA (N-methyl-D-aspartate), KA (kainate), and QA (quisqualate) glutamate neurotransmitter receptor sites. While none of the four analogues binds effectively to the excitatory receptors, the L-trans-isomer 7 is a potent and selective competitive inhibitor of L-glutamate transport. These results delineate a specific structural/conformational preference for binding to the uptake system that is distinct from that required for binding to the NMDA, KA, and QA receptors.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00106a037</identifier><identifier>PMID: 1671706</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Binding, Competitive ; Chemical Phenomena ; Chemistry ; Exact sciences and technology ; Glutamates - pharmacokinetics ; Glutamic Acid ; Heterocyclic compounds ; Heterocyclic compounds with only one n hetero atom and condensed derivatives ; Male ; Molecular Conformation ; N-methyl-D-aspartic acid ; neurons ; Neurotransmitter Agents - chemical synthesis ; Neurotransmitter Agents - pharmacology ; Organic chemistry ; Preparations and properties ; Pyrrolidines - chemical synthesis ; Pyrrolidines - pharmacology ; Rats ; Rats, Inbred Strains ; Receptors, Neurotransmitter - drug effects ; Receptors, Neurotransmitter - metabolism ; Stereoisomerism ; Structure-Activity Relationship ; Synaptosomes - drug effects ; Synaptosomes - metabolism</subject><ispartof>Journal of medicinal chemistry, 1991-02, Vol.34 (2), p.717-725</ispartof><rights>1991 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a481t-879e90e008db0e4a0fe869b68c24e99fa4c3f095520e708bb607285545f3502a3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00106a037$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00106a037$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19599827$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1671706$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bridges, Richard J</creatorcontrib><creatorcontrib>Stanley, Mark S</creatorcontrib><creatorcontrib>Anderson, Michael W</creatorcontrib><creatorcontrib>Cotman, Carl W</creatorcontrib><creatorcontrib>Chamberlin, A. Richard</creatorcontrib><title>Conformationally defined neurotransmitter analogs. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>In order to determine the conformational requirements for binding of L-glutamate to the proteins involved in the process of neurotransmission, rigid analogues containing an embedded glutamate moiety have been prepared. These "conformer mimics", the pyrrolidine-2,4-dicarboxylates 4, 7, 11, and 14, were synthesized from commercially available trans-4-hydroxy-L-proline and cis-4-hydroxy-D-proline, and then were tested for their ability to inhibit the high-affinity transport of [3H]-L-glutamate into synaptosomes and to block the binding of radioligands to the NMDA (N-methyl-D-aspartate), KA (kainate), and QA (quisqualate) glutamate neurotransmitter receptor sites. While none of the four analogues binds effectively to the excitatory receptors, the L-trans-isomer 7 is a potent and selective competitive inhibitor of L-glutamate transport. These results delineate a specific structural/conformational preference for binding to the uptake system that is distinct from that required for binding to the NMDA, KA, and QA receptors.</description><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Exact sciences and technology</subject><subject>Glutamates - pharmacokinetics</subject><subject>Glutamic Acid</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with only one n hetero atom and condensed derivatives</subject><subject>Male</subject><subject>Molecular Conformation</subject><subject>N-methyl-D-aspartic acid</subject><subject>neurons</subject><subject>Neurotransmitter Agents - chemical synthesis</subject><subject>Neurotransmitter Agents - pharmacology</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Pyrrolidines - chemical synthesis</subject><subject>Pyrrolidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Receptors, Neurotransmitter - drug effects</subject><subject>Receptors, Neurotransmitter - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Synaptosomes - drug effects</subject><subject>Synaptosomes - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAURSMEKtPCijWSN9AFpDw7seMs0cAAUiVAHTZsLCd5Lp468dROUPMR_DMeZURZILHy4p53ZN2bZc8oXFBg9M2uB6AgNBTVg2xFOYO8lFA-zFYAjOVMsOJxdhrjDgAKyoqT7ISKilYgVtmvtR-MD70erR-0czPp0NgBOzLgFPwY9BB7O44YiE65v44X5AodtqP9icQOP2xjD6fEG3LtplEnE5JpP-obJM1M_IBkP4fgne2SNmevy7yzrQ6Nv5vdge2sjkmPvsfwJHtktIv49PieZd8277frj_nl5w-f1m8vc11KOuayqrEGBJBdA1hqMChF3QjZshLr2uiyLQzUPDWBFcimEVAxyXnJTcGB6eIse7l498HfThhH1dvYonN6QD9FldrjjAv5X5AKClzwIoGvFrANPsaARu2D7XWYFQV1WEn9tVKinx-1U9Njd88us6T8xTHXsdXOpBVaG--xmte1ZAdPvnA2VXj3J9fhRomqqLjafrlSJf-6efddbtQ28ecLr9uodn4KadL4zx_-Btmbt80</recordid><startdate>19910201</startdate><enddate>19910201</enddate><creator>Bridges, Richard J</creator><creator>Stanley, Mark S</creator><creator>Anderson, Michael W</creator><creator>Cotman, Carl W</creator><creator>Chamberlin, A. Richard</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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>8FD</scope><scope>FR3</scope><scope>M7Z</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>19910201</creationdate><title>Conformationally defined neurotransmitter analogs. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer</title><author>Bridges, Richard J ; Stanley, Mark S ; Anderson, Michael W ; Cotman, Carl W ; Chamberlin, A. Richard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a481t-879e90e008db0e4a0fe869b68c24e99fa4c3f095520e708bb607285545f3502a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Exact sciences and technology</topic><topic>Glutamates - pharmacokinetics</topic><topic>Glutamic Acid</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with only one n hetero atom and condensed derivatives</topic><topic>Male</topic><topic>Molecular Conformation</topic><topic>N-methyl-D-aspartic acid</topic><topic>neurons</topic><topic>Neurotransmitter Agents - chemical synthesis</topic><topic>Neurotransmitter Agents - pharmacology</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Pyrrolidines - chemical synthesis</topic><topic>Pyrrolidines - pharmacology</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Receptors, Neurotransmitter - drug effects</topic><topic>Receptors, Neurotransmitter - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Synaptosomes - drug effects</topic><topic>Synaptosomes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bridges, Richard J</creatorcontrib><creatorcontrib>Stanley, Mark S</creatorcontrib><creatorcontrib>Anderson, Michael W</creatorcontrib><creatorcontrib>Cotman, Carl W</creatorcontrib><creatorcontrib>Chamberlin, A. Richard</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bridges, Richard J</au><au>Stanley, Mark S</au><au>Anderson, Michael W</au><au>Cotman, Carl W</au><au>Chamberlin, A. Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conformationally defined neurotransmitter analogs. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1991-02-01</date><risdate>1991</risdate><volume>34</volume><issue>2</issue><spage>717</spage><epage>725</epage><pages>717-725</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>In order to determine the conformational requirements for binding of L-glutamate to the proteins involved in the process of neurotransmission, rigid analogues containing an embedded glutamate moiety have been prepared. These "conformer mimics", the pyrrolidine-2,4-dicarboxylates 4, 7, 11, and 14, were synthesized from commercially available trans-4-hydroxy-L-proline and cis-4-hydroxy-D-proline, and then were tested for their ability to inhibit the high-affinity transport of [3H]-L-glutamate into synaptosomes and to block the binding of radioligands to the NMDA (N-methyl-D-aspartate), KA (kainate), and QA (quisqualate) glutamate neurotransmitter receptor sites. While none of the four analogues binds effectively to the excitatory receptors, the L-trans-isomer 7 is a potent and selective competitive inhibitor of L-glutamate transport. These results delineate a specific structural/conformational preference for binding to the uptake system that is distinct from that required for binding to the NMDA, KA, and QA receptors.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>1671706</pmid><doi>10.1021/jm00106a037</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Binding, Competitive Chemical Phenomena Chemistry Exact sciences and technology Glutamates - pharmacokinetics Glutamic Acid Heterocyclic compounds Heterocyclic compounds with only one n hetero atom and condensed derivatives Male Molecular Conformation N-methyl-D-aspartic acid neurons Neurotransmitter Agents - chemical synthesis Neurotransmitter Agents - pharmacology Organic chemistry Preparations and properties Pyrrolidines - chemical synthesis Pyrrolidines - pharmacology Rats Rats, Inbred Strains Receptors, Neurotransmitter - drug effects Receptors, Neurotransmitter - metabolism Stereoisomerism Structure-Activity Relationship Synaptosomes - drug effects Synaptosomes - metabolism |
| title | Conformationally defined neurotransmitter analogs. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer |
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