Dicarba Analogues of α‑Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets
α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-12, Vol.57 (23), p.9933-9944 |
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| container_issue | 23 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 57 |
| creator | Chhabra, Sandeep Belgi, Alessia Bartels, Peter van Lierop, Bianca J Robinson, Samuel D Kompella, Shiva N Hung, Andrew Callaghan, Brid P Adams, David J Robinson, Andrea J Norton, Raymond S |
| description | α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors. |
| doi_str_mv | 10.1021/jm501126u |
| format | Article |
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Structure, Stability, and Activity at Potential Pain Targets</title><source>MEDLINE</source><source>ACS Publications</source><creator>Chhabra, Sandeep ; Belgi, Alessia ; Bartels, Peter ; van Lierop, Bianca J ; Robinson, Samuel D ; Kompella, Shiva N ; Hung, Andrew ; Callaghan, Brid P ; Adams, David J ; Robinson, Andrea J ; Norton, Raymond S</creator><creatorcontrib>Chhabra, Sandeep ; Belgi, Alessia ; Bartels, Peter ; van Lierop, Bianca J ; Robinson, Samuel D ; Kompella, Shiva N ; Hung, Andrew ; Callaghan, Brid P ; Adams, David J ; Robinson, Andrea J ; Norton, Raymond S</creatorcontrib><description>α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm501126u</identifier><identifier>PMID: 25393758</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amino Acid Sequence ; Analgesics ; Animals ; Calcium Channels, N-Type - drug effects ; Conotoxins - chemistry ; Conotoxins - pharmacology ; HEK293 Cells ; Humans ; Magnetic Resonance Spectroscopy ; Molecular Dynamics Simulation ; Rats ; Receptors, Nicotinic - drug effects</subject><ispartof>Journal of medicinal chemistry, 2014-12, Vol.57 (23), p.9933-9944</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-d22d06f8f6c2a06b93c5ad6bb96215ad62ee1b566ef2c4eb2a0c1c62fda28aa93</citedby><cites>FETCH-LOGICAL-a315t-d22d06f8f6c2a06b93c5ad6bb96215ad62ee1b566ef2c4eb2a0c1c62fda28aa93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm501126u$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm501126u$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2756,27067,27915,27916,56729,56779</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25393758$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chhabra, Sandeep</creatorcontrib><creatorcontrib>Belgi, Alessia</creatorcontrib><creatorcontrib>Bartels, Peter</creatorcontrib><creatorcontrib>van Lierop, Bianca J</creatorcontrib><creatorcontrib>Robinson, Samuel D</creatorcontrib><creatorcontrib>Kompella, Shiva N</creatorcontrib><creatorcontrib>Hung, Andrew</creatorcontrib><creatorcontrib>Callaghan, Brid P</creatorcontrib><creatorcontrib>Adams, David J</creatorcontrib><creatorcontrib>Robinson, Andrea J</creatorcontrib><creatorcontrib>Norton, Raymond S</creatorcontrib><title>Dicarba Analogues of α‑Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.</description><subject>Amino Acid Sequence</subject><subject>Analgesics</subject><subject>Animals</subject><subject>Calcium Channels, N-Type - drug effects</subject><subject>Conotoxins - chemistry</subject><subject>Conotoxins - pharmacology</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Molecular Dynamics Simulation</subject><subject>Rats</subject><subject>Receptors, Nicotinic - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1OwzAQRi0EoqWw4ALIGySQGrAnjdsuo_JXqRIVlHU0cZwqVRIX20F0xxU4ChfhEJwEVy1dsZpvpDefNI-QU86uOAN-vagixjmIZo-0eQQs6A1Yb5-0GQMIQEDYIkfWLhhjIYfwkLQgCodhPxq0SX5TSDQp0rjGUs8bZanO6ffXz8fnSNfa6feipk_zcXxFn51ppGuM6vqIaVEWbtWlWGc0lq548xtFR6faqdoVWNIp-tMZmrly9pgc5FhadbKdHfJydzsbPQSTx_vxKJ4EGPLIBRlAxkQ-yIUEZCIdhjLCTKTpUABfJ1CKp5EQKgfZU6mHJJcC8gxhgDgMO-Ri07s0-tU_45KqsFKVJdZKNzbhwr8t-kys0csNKo221qg8WZqiQrNKOEvWWpOdVs-ebWubtFLZjvzz6IHzDYDSJgvdGG_T_lP0C5QTgKI</recordid><startdate>20141211</startdate><enddate>20141211</enddate><creator>Chhabra, Sandeep</creator><creator>Belgi, Alessia</creator><creator>Bartels, Peter</creator><creator>van Lierop, Bianca J</creator><creator>Robinson, Samuel D</creator><creator>Kompella, Shiva N</creator><creator>Hung, Andrew</creator><creator>Callaghan, Brid P</creator><creator>Adams, David J</creator><creator>Robinson, Andrea J</creator><creator>Norton, Raymond S</creator><general>American Chemical Society</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>20141211</creationdate><title>Dicarba Analogues of α‑Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets</title><author>Chhabra, Sandeep ; Belgi, Alessia ; Bartels, Peter ; van Lierop, Bianca J ; Robinson, Samuel D ; Kompella, Shiva N ; Hung, Andrew ; Callaghan, Brid P ; Adams, David J ; Robinson, Andrea J ; Norton, Raymond S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-d22d06f8f6c2a06b93c5ad6bb96215ad62ee1b566ef2c4eb2a0c1c62fda28aa93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amino Acid Sequence</topic><topic>Analgesics</topic><topic>Animals</topic><topic>Calcium Channels, N-Type - drug effects</topic><topic>Conotoxins - chemistry</topic><topic>Conotoxins - pharmacology</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Molecular Dynamics Simulation</topic><topic>Rats</topic><topic>Receptors, Nicotinic - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chhabra, Sandeep</creatorcontrib><creatorcontrib>Belgi, Alessia</creatorcontrib><creatorcontrib>Bartels, Peter</creatorcontrib><creatorcontrib>van Lierop, Bianca J</creatorcontrib><creatorcontrib>Robinson, Samuel D</creatorcontrib><creatorcontrib>Kompella, Shiva N</creatorcontrib><creatorcontrib>Hung, Andrew</creatorcontrib><creatorcontrib>Callaghan, Brid P</creatorcontrib><creatorcontrib>Adams, David J</creatorcontrib><creatorcontrib>Robinson, Andrea J</creatorcontrib><creatorcontrib>Norton, Raymond S</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chhabra, Sandeep</au><au>Belgi, Alessia</au><au>Bartels, Peter</au><au>van Lierop, Bianca J</au><au>Robinson, Samuel D</au><au>Kompella, Shiva N</au><au>Hung, Andrew</au><au>Callaghan, Brid P</au><au>Adams, David J</au><au>Robinson, Andrea J</au><au>Norton, Raymond S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dicarba Analogues of α‑Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-12-11</date><risdate>2014</risdate><volume>57</volume><issue>23</issue><spage>9933</spage><epage>9944</epage><pages>9933-9944</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25393758</pmid><doi>10.1021/jm501126u</doi><tpages>12</tpages></addata></record> |
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| subjects | Amino Acid Sequence Analgesics Animals Calcium Channels, N-Type - drug effects Conotoxins - chemistry Conotoxins - pharmacology HEK293 Cells Humans Magnetic Resonance Spectroscopy Molecular Dynamics Simulation Rats Receptors, Nicotinic - drug effects |
| title | Dicarba Analogues of α‑Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets |
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