Carborane-Derived Local Anesthetics are Isomer Dependent
Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho‐, meta‐, C,C’‐dimethyl m...
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| Veröffentlicht in: | ChemMedChem 2015-01, Vol.10 (1), p.62-67 |
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| creator | Kracke, George R. VanGordon, Monika R. Sevryugina, Yulia V. Kueffer, Peter J. Kabytaev, Kuanysh Jalisatgi, Satish S. Hawthorne, M. Frederick |
| description | Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho‐, meta‐, C,C’‐dimethyl meta‐ and para‐carborane clusters. The boronicaine derivatives were tested for their analgesic activity and compared with lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho‐carborane = C,C’‐dimethyl meta‐carborane > para‐carborane > lidocaine > meta‐carborane derivative. Both ortho‐boronicaine and C,C’‐dimethyl meta‐boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics.
Cage anesthetics: In a new local anesthetic, ortho‐boronicaine, the phenyl ring of lidocaine was replaced with a highly symmetric, ortho‐carborane cage. Hindlimb plantar injections in mice resulted in longer analgesic effects compared with lidocaine. ortho‐Boronicaine exhibited greater analgesic efficacy compared with lidocaine or the meta‐ and para‐carborane or adamantane derivatives. |
| doi_str_mv | 10.1002/cmdc.201402369 |
| format | Article |
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Cage anesthetics: In a new local anesthetic, ortho‐boronicaine, the phenyl ring of lidocaine was replaced with a highly symmetric, ortho‐carborane cage. Hindlimb plantar injections in mice resulted in longer analgesic effects compared with lidocaine. ortho‐Boronicaine exhibited greater analgesic efficacy compared with lidocaine or the meta‐ and para‐carborane or adamantane derivatives.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201402369</identifier><identifier>PMID: 25420874</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>Analgesics ; Anesthetics, Local - chemical synthesis ; Anesthetics, Local - chemistry ; Anesthetics, Local - therapeutic use ; Animals ; Area Under Curve ; Binding Sites ; Boranes - chemical synthesis ; Boranes - chemistry ; Boranes - therapeutic use ; carboranes ; Catalysis ; Catalytic Domain ; Humans ; Isomerism ; lidocaine ; Lidocaine - chemistry ; local anesthetic agents ; Mice ; Molecular Docking Simulation ; pain ; Pain - drug therapy ; Palladium - chemistry ; ROC Curve ; sensory blockade ; Serum Albumin - chemistry ; Serum Albumin - metabolism</subject><ispartof>ChemMedChem, 2015-01, Vol.10 (1), p.62-67</ispartof><rights>2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4119-2cd45ab270e3ac48b1affe65a70428ccd46e82f2dab8e5c307a33b241e9948583</citedby><cites>FETCH-LOGICAL-c4119-2cd45ab270e3ac48b1affe65a70428ccd46e82f2dab8e5c307a33b241e9948583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201402369$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201402369$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25420874$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kracke, George R.</creatorcontrib><creatorcontrib>VanGordon, Monika R.</creatorcontrib><creatorcontrib>Sevryugina, Yulia V.</creatorcontrib><creatorcontrib>Kueffer, Peter J.</creatorcontrib><creatorcontrib>Kabytaev, Kuanysh</creatorcontrib><creatorcontrib>Jalisatgi, Satish S.</creatorcontrib><creatorcontrib>Hawthorne, M. Frederick</creatorcontrib><title>Carborane-Derived Local Anesthetics are Isomer Dependent</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho‐, meta‐, C,C’‐dimethyl meta‐ and para‐carborane clusters. The boronicaine derivatives were tested for their analgesic activity and compared with lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho‐carborane = C,C’‐dimethyl meta‐carborane > para‐carborane > lidocaine > meta‐carborane derivative. Both ortho‐boronicaine and C,C’‐dimethyl meta‐boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics.
Cage anesthetics: In a new local anesthetic, ortho‐boronicaine, the phenyl ring of lidocaine was replaced with a highly symmetric, ortho‐carborane cage. Hindlimb plantar injections in mice resulted in longer analgesic effects compared with lidocaine. ortho‐Boronicaine exhibited greater analgesic efficacy compared with lidocaine or the meta‐ and para‐carborane or adamantane derivatives.</description><subject>Analgesics</subject><subject>Anesthetics, Local - chemical synthesis</subject><subject>Anesthetics, Local - chemistry</subject><subject>Anesthetics, Local - therapeutic use</subject><subject>Animals</subject><subject>Area Under Curve</subject><subject>Binding Sites</subject><subject>Boranes - chemical synthesis</subject><subject>Boranes - chemistry</subject><subject>Boranes - therapeutic use</subject><subject>carboranes</subject><subject>Catalysis</subject><subject>Catalytic Domain</subject><subject>Humans</subject><subject>Isomerism</subject><subject>lidocaine</subject><subject>Lidocaine - chemistry</subject><subject>local anesthetic agents</subject><subject>Mice</subject><subject>Molecular Docking Simulation</subject><subject>pain</subject><subject>Pain - drug therapy</subject><subject>Palladium - chemistry</subject><subject>ROC Curve</subject><subject>sensory blockade</subject><subject>Serum Albumin - chemistry</subject><subject>Serum Albumin - metabolism</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtLAzEUhYMovrcuZcCNm6l5zSRZlqnWQlUQte5CJnMHp86jJq3af2-ktYgbV7mQ7xwOH0InBPcIxvTCNoXtUUw4pixVW2ifyBTHgkixvbmF2kMH3k8x5lwSuYv2aMIploLvI5kZl3fOtBAPwFXvUETjzpo66rfg5y8wr6yPjINo5LsGXDSAGbQFtPMjtFOa2sPx-j1Ej1eXD9l1PL4bjrL-OLacEBVTW_DE5FRgYMZymRNTlpAmRmBOpQ2_KUha0sLkEhLLsDCM5ZQTUIrLRLJDdL7qnbnubRE26abyFuo6TO4WXpOUY0YFT3lAz_6g027h2rAuUExRxRWjgeqtKOs67x2UeuaqxrilJlh_O9XfTvXGaQicrmsXeQPFBv-RGAC1Aj6qGpb_1OnsZpD9Lo9X2crP4XOTNe5Vp4KJRE9uh5o93yTD-8mTnrAv_uiQZA</recordid><startdate>201501</startdate><enddate>201501</enddate><creator>Kracke, George R.</creator><creator>VanGordon, Monika R.</creator><creator>Sevryugina, Yulia V.</creator><creator>Kueffer, Peter J.</creator><creator>Kabytaev, Kuanysh</creator><creator>Jalisatgi, Satish S.</creator><creator>Hawthorne, M. Frederick</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201501</creationdate><title>Carborane-Derived Local Anesthetics are Isomer Dependent</title><author>Kracke, George R. ; VanGordon, Monika R. ; Sevryugina, Yulia V. ; Kueffer, Peter J. ; Kabytaev, Kuanysh ; Jalisatgi, Satish S. ; Hawthorne, M. Frederick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4119-2cd45ab270e3ac48b1affe65a70428ccd46e82f2dab8e5c307a33b241e9948583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Analgesics</topic><topic>Anesthetics, Local - chemical synthesis</topic><topic>Anesthetics, Local - chemistry</topic><topic>Anesthetics, Local - therapeutic use</topic><topic>Animals</topic><topic>Area Under Curve</topic><topic>Binding Sites</topic><topic>Boranes - chemical synthesis</topic><topic>Boranes - chemistry</topic><topic>Boranes - therapeutic use</topic><topic>carboranes</topic><topic>Catalysis</topic><topic>Catalytic Domain</topic><topic>Humans</topic><topic>Isomerism</topic><topic>lidocaine</topic><topic>Lidocaine - chemistry</topic><topic>local anesthetic agents</topic><topic>Mice</topic><topic>Molecular Docking Simulation</topic><topic>pain</topic><topic>Pain - drug therapy</topic><topic>Palladium - chemistry</topic><topic>ROC Curve</topic><topic>sensory blockade</topic><topic>Serum Albumin - chemistry</topic><topic>Serum Albumin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kracke, George R.</creatorcontrib><creatorcontrib>VanGordon, Monika R.</creatorcontrib><creatorcontrib>Sevryugina, Yulia V.</creatorcontrib><creatorcontrib>Kueffer, Peter J.</creatorcontrib><creatorcontrib>Kabytaev, Kuanysh</creatorcontrib><creatorcontrib>Jalisatgi, Satish S.</creatorcontrib><creatorcontrib>Hawthorne, M. Frederick</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kracke, George R.</au><au>VanGordon, Monika R.</au><au>Sevryugina, Yulia V.</au><au>Kueffer, Peter J.</au><au>Kabytaev, Kuanysh</au><au>Jalisatgi, Satish S.</au><au>Hawthorne, M. Frederick</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Carborane-Derived Local Anesthetics are Isomer Dependent</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2015-01</date><risdate>2015</risdate><volume>10</volume><issue>1</issue><spage>62</spage><epage>67</epage><pages>62-67</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho‐, meta‐, C,C’‐dimethyl meta‐ and para‐carborane clusters. The boronicaine derivatives were tested for their analgesic activity and compared with lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho‐carborane = C,C’‐dimethyl meta‐carborane > para‐carborane > lidocaine > meta‐carborane derivative. Both ortho‐boronicaine and C,C’‐dimethyl meta‐boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics.
Cage anesthetics: In a new local anesthetic, ortho‐boronicaine, the phenyl ring of lidocaine was replaced with a highly symmetric, ortho‐carborane cage. Hindlimb plantar injections in mice resulted in longer analgesic effects compared with lidocaine. ortho‐Boronicaine exhibited greater analgesic efficacy compared with lidocaine or the meta‐ and para‐carborane or adamantane derivatives.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>25420874</pmid><doi>10.1002/cmdc.201402369</doi><tpages>6</tpages></addata></record> |
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| subjects | Analgesics Anesthetics, Local - chemical synthesis Anesthetics, Local - chemistry Anesthetics, Local - therapeutic use Animals Area Under Curve Binding Sites Boranes - chemical synthesis Boranes - chemistry Boranes - therapeutic use carboranes Catalysis Catalytic Domain Humans Isomerism lidocaine Lidocaine - chemistry local anesthetic agents Mice Molecular Docking Simulation pain Pain - drug therapy Palladium - chemistry ROC Curve sensory blockade Serum Albumin - chemistry Serum Albumin - metabolism |
| title | Carborane-Derived Local Anesthetics are Isomer Dependent |
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