High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor
The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the hum...
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| Veröffentlicht in: | Journal of medicinal chemistry 2000-04, Vol.43 (7), p.1329-1338 |
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| container_title | Journal of medicinal chemistry |
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| creator | Röver, Stephan Adam, Geo Cesura, Andrea M Galley, Guido Jenck, François Monsma, Frederick J Wichmann, Jürgen Dautzenberg, Frank M |
| description | The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure−activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors. |
| doi_str_mv | 10.1021/jm991129q |
| format | Article |
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These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure−activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm991129q</identifier><identifier>PMID: 10753470</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Binding, Competitive ; Biological and medical sciences ; Cell Line ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Ligands ; Medical sciences ; Neuropharmacology ; Neurotransmitters. 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Drug treatments ; Radioligand Assay ; Receptors, Opioid - agonists ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Spiro Compounds - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2000-04, Vol.43 (7), p.1329-1338</ispartof><rights>Copyright © 2000 American Chemical Society</rights><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a469t-e2b9a3fa1181de3e1867ec10887c75cf211837bff7dcad82832fe84ef1dd62b23</citedby><cites>FETCH-LOGICAL-a469t-e2b9a3fa1181de3e1867ec10887c75cf211837bff7dcad82832fe84ef1dd62b23</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/jm991129q$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm991129q$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1345474$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10753470$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Röver, Stephan</creatorcontrib><creatorcontrib>Adam, Geo</creatorcontrib><creatorcontrib>Cesura, Andrea M</creatorcontrib><creatorcontrib>Galley, Guido</creatorcontrib><creatorcontrib>Jenck, François</creatorcontrib><creatorcontrib>Monsma, Frederick J</creatorcontrib><creatorcontrib>Wichmann, Jürgen</creatorcontrib><creatorcontrib>Dautzenberg, Frank M</creatorcontrib><title>High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure−activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors.</description><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Radioligand Assay</subject><subject>Receptors, Opioid - agonists</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - chemistry</subject><subject>Spiro Compounds - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MtOGzEUgGELUUGgXfQF0CxoVaQO-DZjzzJCpFSKCKSA2FmO55g4JHawJ1J5-zqaiHbRlS2dT0f2j9Bngs8JpuRisWoaQmjzuocGpKK45BLzfTTAmNKS1pQdoqOUFhhjRig7QIcEi4pxgQdoeu2e5-XQWudd9_a9uAm-vIV151oohs_Bu9SlwoZYdHMoJtMxKb5N4nquvfPF6O7iJhhnttyfFVPY3kL8iD5YvUzwaXceo4fR1f3ldTme_Ph5ORyXmtdNVwKdNZpZTYgkLTAgshZgCJZSGFEZS_OAiZm1ojW6lVQyakFysKRtazqj7Bh97feuY3jdQOrUyiUDy6X2EDZJCVrx_FGZ4VkPTQwpRbBqHd1KxzdFsNoGVO8Bsz3ZLd3MVtD-I_tiGZzugE5GL23U3rj01zFeccEzK3uWA8Lv97GOL6oWTFTq_vaXYqNH1jw-UcWy_9J7bZJahE30Od1_3vcHPfuRgA</recordid><startdate>20000406</startdate><enddate>20000406</enddate><creator>Röver, Stephan</creator><creator>Adam, Geo</creator><creator>Cesura, Andrea M</creator><creator>Galley, Guido</creator><creator>Jenck, François</creator><creator>Monsma, Frederick J</creator><creator>Wichmann, Jürgen</creator><creator>Dautzenberg, Frank M</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>7X8</scope></search><sort><creationdate>20000406</creationdate><title>High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor</title><author>Röver, Stephan ; Adam, Geo ; Cesura, Andrea M ; Galley, Guido ; Jenck, François ; Monsma, Frederick J ; Wichmann, Jürgen ; Dautzenberg, Frank M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a469t-e2b9a3fa1181de3e1867ec10887c75cf211837bff7dcad82832fe84ef1dd62b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Radioligand Assay</topic><topic>Receptors, Opioid - agonists</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - chemistry</topic><topic>Spiro Compounds - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Röver, Stephan</creatorcontrib><creatorcontrib>Adam, Geo</creatorcontrib><creatorcontrib>Cesura, Andrea M</creatorcontrib><creatorcontrib>Galley, Guido</creatorcontrib><creatorcontrib>Jenck, François</creatorcontrib><creatorcontrib>Monsma, Frederick J</creatorcontrib><creatorcontrib>Wichmann, Jürgen</creatorcontrib><creatorcontrib>Dautzenberg, Frank M</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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Röver, Stephan</au><au>Adam, Geo</au><au>Cesura, Andrea M</au><au>Galley, Guido</au><au>Jenck, François</au><au>Monsma, Frederick J</au><au>Wichmann, Jürgen</au><au>Dautzenberg, Frank M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2000-04-06</date><risdate>2000</risdate><volume>43</volume><issue>7</issue><spage>1329</spage><epage>1338</epage><pages>1329-1338</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure−activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>10753470</pmid><doi>10.1021/jm991129q</doi><tpages>10</tpages></addata></record> |
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| subjects | Binding, Competitive Biological and medical sciences Cell Line Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Ligands Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Radioligand Assay Receptors, Opioid - agonists Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacology Structure-Activity Relationship |
| title | High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor |
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