Tetrapeptide inhibitors of the glutamate vesicular transporter (VGLUT)
Quinoline-2,4-dicarboxylic acids (QDCs) bearing lipophilic substituents in the 6- or 7-position were shown to be inhibitors of the glutamate vesicular transporter (VGLUT). Using the arrangement of the QDC lipophilic substituents as a template, libraries of X 1X 2EF and X 1X 2EW tetrapeptides were sy...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007-09, Vol.17 (18), p.5125-5128 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Patel, Sarjubhai A. Nagy, Jon O. Bolstad, Erin D. Gerdes, John M. Thompson, Charles M. |
| description | Quinoline-2,4-dicarboxylic acids (QDCs) bearing lipophilic substituents in the 6- or 7-position were shown to be inhibitors of the glutamate vesicular transporter (VGLUT). Using the arrangement of the QDC lipophilic substituents as a template, libraries of X
1X
2EF and X
1X
2EW tetrapeptides were synthesized and tested as VGLUT inhibitors. The peptides QIEW and WNEF were found to be the most potent. Further stereochemical deconvolution of these two peptides showed
dQ
lI
dE
lW to be the best inhibitor (
K
i
=
828
±
252
μM). Modeling and overlay of the tetrapeptide inhibitors with the existing pharmacophore showed that H-bonding and lipophilic residues are important for VGLUT binding. |
| doi_str_mv | 10.1016/j.bmcl.2007.07.006 |
| format | Article |
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1X
2EF and X
1X
2EW tetrapeptides were synthesized and tested as VGLUT inhibitors. The peptides QIEW and WNEF were found to be the most potent. Further stereochemical deconvolution of these two peptides showed
dQ
lI
dE
lW to be the best inhibitor (
K
i
=
828
±
252
μM). Modeling and overlay of the tetrapeptide inhibitors with the existing pharmacophore showed that H-bonding and lipophilic residues are important for VGLUT binding.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2007.07.006</identifier><identifier>PMID: 17662605</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Biological and medical sciences ; Glutamate ; Glutamatergic system (aspartate and other excitatory aminoacids) ; Inhibitor ; Medical sciences ; Models, Molecular ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Oligopeptides - pharmacology ; Pharmacology. Drug treatments ; Tetrapeptides ; Trypan blue ; Uptake ; Vesicle ; Vesicular glutamate transporter (VGLUT) ; Vesicular Inhibitory Amino Acid Transport Proteins - antagonists & inhibitors</subject><ispartof>Bioorganic & medicinal chemistry letters, 2007-09, Vol.17 (18), p.5125-5128</ispartof><rights>2007 Elsevier Ltd</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c549t-388a115c9eceef03179121f980bc800a41438303e23514f11978d5fbbd8eca643</citedby><cites>FETCH-LOGICAL-c549t-388a115c9eceef03179121f980bc800a41438303e23514f11978d5fbbd8eca643</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X07008062$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19021272$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17662605$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Patel, Sarjubhai A.</creatorcontrib><creatorcontrib>Nagy, Jon O.</creatorcontrib><creatorcontrib>Bolstad, Erin D.</creatorcontrib><creatorcontrib>Gerdes, John M.</creatorcontrib><creatorcontrib>Thompson, Charles M.</creatorcontrib><title>Tetrapeptide inhibitors of the glutamate vesicular transporter (VGLUT)</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Quinoline-2,4-dicarboxylic acids (QDCs) bearing lipophilic substituents in the 6- or 7-position were shown to be inhibitors of the glutamate vesicular transporter (VGLUT). Using the arrangement of the QDC lipophilic substituents as a template, libraries of X
1X
2EF and X
1X
2EW tetrapeptides were synthesized and tested as VGLUT inhibitors. The peptides QIEW and WNEF were found to be the most potent. Further stereochemical deconvolution of these two peptides showed
dQ
lI
dE
lW to be the best inhibitor (
K
i
=
828
±
252
μM). Modeling and overlay of the tetrapeptide inhibitors with the existing pharmacophore showed that H-bonding and lipophilic residues are important for VGLUT binding.</description><subject>Biological and medical sciences</subject><subject>Glutamate</subject><subject>Glutamatergic system (aspartate and other excitatory aminoacids)</subject><subject>Inhibitor</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Oligopeptides - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Tetrapeptides</subject><subject>Trypan blue</subject><subject>Uptake</subject><subject>Vesicle</subject><subject>Vesicular glutamate transporter (VGLUT)</subject><subject>Vesicular Inhibitory Amino Acid Transport Proteins - antagonists & inhibitors</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2LFDEQhoMo7uzqH_AgfVH0MGNVdzqdgAiy7K7CgJdZ8RbS6eqdDP1lkh7w35tmBlcvQkEd8tSbl4exVwgbBBQfDpu6t90mB6g2y4B4wlbIBV8XHMqnbAVKwFoq_uOCXYZwAEAOnD9nF1gJkQsoV-x2R9GbiaboGsrcsHe1i6MP2dhmcU_ZQzdH05tI2ZGCs3NnfJYOhjCNPpLP3n2_297v3r9gz1rTBXp53lfs_vZmd_1lvf129_X683ZtS67iupDSIJZWkSVqocBKYY6tklBbCWA48kIWUFBelMhbRFXJpmzrupFkjeDFFft0yp3muqfG0pDKdHryrjf-lx6N0_--DG6vH8ajTpIwV0UKeHsO8OPPmULUvQuWus4MNM5BC4lSlQAJzE-g9WMInto_nyDoRb8-6EX_klzpZUCko9d_13s8OftOwJszYII1XZtMWhceOQU55lWeuI8njpLMoyOvg3U0WGqcJxt1M7r_9fgNkvCj-A</recordid><startdate>20070915</startdate><enddate>20070915</enddate><creator>Patel, Sarjubhai A.</creator><creator>Nagy, Jon O.</creator><creator>Bolstad, Erin D.</creator><creator>Gerdes, John M.</creator><creator>Thompson, Charles M.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20070915</creationdate><title>Tetrapeptide inhibitors of the glutamate vesicular transporter (VGLUT)</title><author>Patel, Sarjubhai A. ; Nagy, Jon O. ; Bolstad, Erin D. ; Gerdes, John M. ; Thompson, Charles M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c549t-388a115c9eceef03179121f980bc800a41438303e23514f11978d5fbbd8eca643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Biological and medical sciences</topic><topic>Glutamate</topic><topic>Glutamatergic system (aspartate and other excitatory aminoacids)</topic><topic>Inhibitor</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Oligopeptides - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Tetrapeptides</topic><topic>Trypan blue</topic><topic>Uptake</topic><topic>Vesicle</topic><topic>Vesicular glutamate transporter (VGLUT)</topic><topic>Vesicular Inhibitory Amino Acid Transport Proteins - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Patel, Sarjubhai A.</creatorcontrib><creatorcontrib>Nagy, Jon O.</creatorcontrib><creatorcontrib>Bolstad, Erin D.</creatorcontrib><creatorcontrib>Gerdes, John M.</creatorcontrib><creatorcontrib>Thompson, Charles M.</creatorcontrib><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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Patel, Sarjubhai A.</au><au>Nagy, Jon O.</au><au>Bolstad, Erin D.</au><au>Gerdes, John M.</au><au>Thompson, Charles M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tetrapeptide inhibitors of the glutamate vesicular transporter (VGLUT)</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2007-09-15</date><risdate>2007</risdate><volume>17</volume><issue>18</issue><spage>5125</spage><epage>5128</epage><pages>5125-5128</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Quinoline-2,4-dicarboxylic acids (QDCs) bearing lipophilic substituents in the 6- or 7-position were shown to be inhibitors of the glutamate vesicular transporter (VGLUT). Using the arrangement of the QDC lipophilic substituents as a template, libraries of X
1X
2EF and X
1X
2EW tetrapeptides were synthesized and tested as VGLUT inhibitors. The peptides QIEW and WNEF were found to be the most potent. Further stereochemical deconvolution of these two peptides showed
dQ
lI
dE
lW to be the best inhibitor (
K
i
=
828
±
252
μM). Modeling and overlay of the tetrapeptide inhibitors with the existing pharmacophore showed that H-bonding and lipophilic residues are important for VGLUT binding.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>17662605</pmid><doi>10.1016/j.bmcl.2007.07.006</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2007-09, Vol.17 (18), p.5125-5128 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2001293 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Biological and medical sciences Glutamate Glutamatergic system (aspartate and other excitatory aminoacids) Inhibitor Medical sciences Models, Molecular Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Oligopeptides - pharmacology Pharmacology. Drug treatments Tetrapeptides Trypan blue Uptake Vesicle Vesicular glutamate transporter (VGLUT) Vesicular Inhibitory Amino Acid Transport Proteins - antagonists & inhibitors |
| title | Tetrapeptide inhibitors of the glutamate vesicular transporter (VGLUT) |
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