Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2‑Phenylindole Privileged Structure Scaffold
G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1–...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-11, Vol.58 (22), p.8938-8951 |
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| container_issue | 22 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 58 |
| creator | Johansson, Henrik Boesgaard, Michael Worch Nørskov-Lauritsen, Lenea Larsen, Inna Kuhne, Sebastiaan Gloriam, David E Bräuner-Osborne, Hans Sejer Pedersen, Daniel |
| description | G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1–3). Herein, we present the first structure–activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date. |
| doi_str_mv | 10.1021/acs.jmedchem.5b01254 |
| format | Article |
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In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.5b01254</identifier><identifier>PMID: 26516782</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cell Line ; CHO Cells ; Cricetinae ; Cricetulus ; Cyclization ; Drug Design ; Goldfish ; HEK293 Cells ; Humans ; Indoles - chemical synthesis ; Indoles - pharmacology ; Inosine Monophosphate - metabolism ; Ligands ; Mice ; Rats ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Structure-Activity Relationship ; Transfection</subject><ispartof>Journal of medicinal chemistry, 2015-11, Vol.58 (22), p.8938-8951</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-60a5ecccb3a17e74b3b5a53b61249f23c3bd59c3484e03078ef0f39ddabd60723</citedby><cites>FETCH-LOGICAL-a348t-60a5ecccb3a17e74b3b5a53b61249f23c3bd59c3484e03078ef0f39ddabd60723</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/acs.jmedchem.5b01254$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01254$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,778,782,2754,27063,27911,27912,56725,56775</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26516782$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Johansson, Henrik</creatorcontrib><creatorcontrib>Boesgaard, Michael Worch</creatorcontrib><creatorcontrib>Nørskov-Lauritsen, Lenea</creatorcontrib><creatorcontrib>Larsen, Inna</creatorcontrib><creatorcontrib>Kuhne, Sebastiaan</creatorcontrib><creatorcontrib>Gloriam, David E</creatorcontrib><creatorcontrib>Bräuner-Osborne, Hans</creatorcontrib><creatorcontrib>Sejer Pedersen, Daniel</creatorcontrib><title>Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2‑Phenylindole Privileged Structure Scaffold</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1–3). Herein, we present the first structure–activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.</description><subject>Animals</subject><subject>Cell Line</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cyclization</subject><subject>Drug Design</subject><subject>Goldfish</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - pharmacology</subject><subject>Inosine Monophosphate - metabolism</subject><subject>Ligands</subject><subject>Mice</subject><subject>Rats</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Transfection</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFO4zAQhi3ECkrhDRDykUu6Yztx2mOpoCAhbdXuniPHmVAjNy62g8SNE3dekSfBS8se9zTSzPf_o5mfkHMGIwac_VQ6jB432Og1bkZFDYwX-QEZsIJDlo8hPyQDAM4zLrk4JichPAKAYFwckWMuCybLMR-QtxVa1NE8I51a60JEbzSddlE9uM6EGGjrPI1rpHO68C6i6bKZ67cWG7pEjduYxvPFcian9EqF1HXdF84_Xt8Xa-xerOkaZzGpzbOx-JCQVfS9jr1HutKqbZ1tTsmPVtmAZ_s6JH9urn_PbrP7X_O72fQ-UyIfx0yCKlBrXQvFSizzWtSFKkQtGc8nLRda1E0x0YnNEQSUY2yhFZOmUXUjoeRiSC53vlvvnnoMsdqYoNFa1aHrQ8VKIWVZSmAJzXeo9i4Ej2219Waj_EvFoPqbQJUSqL4TqPYJJNnFfkNfp9k_0ffLEwA74Evuet-lg__v-Qnti5fU</recordid><startdate>20151125</startdate><enddate>20151125</enddate><creator>Johansson, Henrik</creator><creator>Boesgaard, Michael Worch</creator><creator>Nørskov-Lauritsen, Lenea</creator><creator>Larsen, Inna</creator><creator>Kuhne, Sebastiaan</creator><creator>Gloriam, David E</creator><creator>Bräuner-Osborne, Hans</creator><creator>Sejer Pedersen, Daniel</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>20151125</creationdate><title>Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2‑Phenylindole Privileged Structure Scaffold</title><author>Johansson, Henrik ; Boesgaard, Michael Worch ; Nørskov-Lauritsen, Lenea ; Larsen, Inna ; Kuhne, Sebastiaan ; Gloriam, David E ; Bräuner-Osborne, Hans ; Sejer Pedersen, Daniel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-60a5ecccb3a17e74b3b5a53b61249f23c3bd59c3484e03078ef0f39ddabd60723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cyclization</topic><topic>Drug Design</topic><topic>Goldfish</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - pharmacology</topic><topic>Inosine Monophosphate - metabolism</topic><topic>Ligands</topic><topic>Mice</topic><topic>Rats</topic><topic>Receptors, G-Protein-Coupled - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johansson, Henrik</creatorcontrib><creatorcontrib>Boesgaard, Michael Worch</creatorcontrib><creatorcontrib>Nørskov-Lauritsen, Lenea</creatorcontrib><creatorcontrib>Larsen, Inna</creatorcontrib><creatorcontrib>Kuhne, Sebastiaan</creatorcontrib><creatorcontrib>Gloriam, David E</creatorcontrib><creatorcontrib>Bräuner-Osborne, Hans</creatorcontrib><creatorcontrib>Sejer Pedersen, Daniel</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>Johansson, Henrik</au><au>Boesgaard, Michael Worch</au><au>Nørskov-Lauritsen, Lenea</au><au>Larsen, Inna</au><au>Kuhne, Sebastiaan</au><au>Gloriam, David E</au><au>Bräuner-Osborne, Hans</au><au>Sejer Pedersen, Daniel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2‑Phenylindole Privileged Structure Scaffold</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2015-11-25</date><risdate>2015</risdate><volume>58</volume><issue>22</issue><spage>8938</spage><epage>8951</epage><pages>8938-8951</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1–3). Herein, we present the first structure–activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26516782</pmid><doi>10.1021/acs.jmedchem.5b01254</doi><tpages>14</tpages></addata></record> |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Cell Line CHO Cells Cricetinae Cricetulus Cyclization Drug Design Goldfish HEK293 Cells Humans Indoles - chemical synthesis Indoles - pharmacology Inosine Monophosphate - metabolism Ligands Mice Rats Receptors, G-Protein-Coupled - antagonists & inhibitors Structure-Activity Relationship Transfection |
| title | Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2‑Phenylindole Privileged Structure Scaffold |
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