δ Opioid Affinity and Selectivity of 4-Hydroxy-3-methoxyindolomorphinan Analogues Related to Naltrindole
To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 1999-05, Vol.42 (9), p.1673-1679 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1679 |
|---|---|
| container_issue | 9 |
| container_start_page | 1673 |
| container_title | Journal of medicinal chemistry |
| container_volume | 42 |
| creator | Coop, Andrew Rothman, Richard B Dersch, Christina Partilla, John Porreca, Frank Davis, Peg Jacobson, Arthur E Rice, Kenner C |
| description | To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2‘,3‘-indolomorphinan (13) was an exception, displaying excellent δ binding selectivity (δ K i = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-γ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity. |
| doi_str_mv | 10.1021/jm9807003 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_69738020</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>69738020</sourcerecordid><originalsourceid>FETCH-LOGICAL-a310t-f436cee3bda575fc149437962021f0ede5ac47c9e01bbd827289cafd64a4087a3</originalsourceid><addsrcrecordid>eNpt0MtuEzEUBmALgWgoLHgB5AUgdTHF48t4ZhlFvSBVbaFhbZ34Qh1mxsF2qua9eA6eqS4TFRasbMvfOTrnR-htTY5rQutP66FriSSEPUOzWlBS8Zbw52hGCKUVbSg7QK9SWpMiaspeooNSRbuGNTPkf__CVxsfvMFz5_zo8w7DaPCN7a3O_u7xHRzm1fnOxHC_q1g12Hxbbn40oQ9DiJtbP8KI5yP04fvWJvzV9pCtwTngS-hz_CPta_TCQZ_sm_15iL6dniwX59XF1dnnxfyiAlaTXDnOGm0tWxkQUjhd844z2TW0LOqINVaA5lJ3ltSrlWmppG2nwZmGAyetBHaIPk59NzH8LONkNfikbd_DaMM2qaaTrCWUFHg0QR1DStE6tYl-gLhTNVGPuaqnXIt9t2-6XQ3W_COnIAt4vweQNPQuwqh9-utaLoToCqsm5lO290_fEH-oRjIp1PL6Rn2RZ5di0Z2qZfEfJg86qXXYxhJy-s98D4pdm-I</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>69738020</pqid></control><display><type>article</type><title>δ Opioid Affinity and Selectivity of 4-Hydroxy-3-methoxyindolomorphinan Analogues Related to Naltrindole</title><source>MEDLINE</source><source>ACS Publications</source><creator>Coop, Andrew ; Rothman, Richard B ; Dersch, Christina ; Partilla, John ; Porreca, Frank ; Davis, Peg ; Jacobson, Arthur E ; Rice, Kenner C</creator><creatorcontrib>Coop, Andrew ; Rothman, Richard B ; Dersch, Christina ; Partilla, John ; Porreca, Frank ; Davis, Peg ; Jacobson, Arthur E ; Rice, Kenner C</creatorcontrib><description>To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2‘,3‘-indolomorphinan (13) was an exception, displaying excellent δ binding selectivity (δ K i = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-γ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm9807003</identifier><identifier>PMID: 10229636</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Binding, Competitive ; Biological and medical sciences ; Brain - metabolism ; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism ; Ileum - drug effects ; Ileum - physiology ; In Vitro Techniques ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Ligands ; Male ; Medical sciences ; Mice ; Mice, Inbred ICR ; Muscle Contraction - drug effects ; Muscle, Smooth - drug effects ; Muscle, Smooth - physiology ; Naltrexone - analogs & derivatives ; Naltrexone - chemical synthesis ; Naltrexone - chemistry ; Naltrexone - pharmacology ; Narcotic Antagonists - chemical synthesis ; Narcotic Antagonists - chemistry ; Narcotic Antagonists - pharmacology ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Rabbits ; Receptors, Opioid, delta - antagonists & inhibitors ; Receptors, Opioid, delta - metabolism ; Vas Deferens - drug effects ; Vas Deferens - physiology</subject><ispartof>Journal of medicinal chemistry, 1999-05, Vol.42 (9), p.1673-1679</ispartof><rights>Copyright © 1999 American Chemical Society</rights><rights>1999 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a310t-f436cee3bda575fc149437962021f0ede5ac47c9e01bbd827289cafd64a4087a3</citedby><cites>FETCH-LOGICAL-a310t-f436cee3bda575fc149437962021f0ede5ac47c9e01bbd827289cafd64a4087a3</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/jm9807003$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm9807003$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1845559$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10229636$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coop, Andrew</creatorcontrib><creatorcontrib>Rothman, Richard B</creatorcontrib><creatorcontrib>Dersch, Christina</creatorcontrib><creatorcontrib>Partilla, John</creatorcontrib><creatorcontrib>Porreca, Frank</creatorcontrib><creatorcontrib>Davis, Peg</creatorcontrib><creatorcontrib>Jacobson, Arthur E</creatorcontrib><creatorcontrib>Rice, Kenner C</creatorcontrib><title>δ Opioid Affinity and Selectivity of 4-Hydroxy-3-methoxyindolomorphinan Analogues Related to Naltrindole</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2‘,3‘-indolomorphinan (13) was an exception, displaying excellent δ binding selectivity (δ K i = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-γ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity.</description><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Guanosine 5'-O-(3-Thiotriphosphate) - metabolism</subject><subject>Ileum - drug effects</subject><subject>Ileum - physiology</subject><subject>In Vitro Techniques</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Ligands</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Muscle Contraction - drug effects</subject><subject>Muscle, Smooth - drug effects</subject><subject>Muscle, Smooth - physiology</subject><subject>Naltrexone - analogs & derivatives</subject><subject>Naltrexone - chemical synthesis</subject><subject>Naltrexone - chemistry</subject><subject>Naltrexone - pharmacology</subject><subject>Narcotic Antagonists - chemical synthesis</subject><subject>Narcotic Antagonists - chemistry</subject><subject>Narcotic Antagonists - pharmacology</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>Rabbits</subject><subject>Receptors, Opioid, delta - antagonists & inhibitors</subject><subject>Receptors, Opioid, delta - metabolism</subject><subject>Vas Deferens - drug effects</subject><subject>Vas Deferens - physiology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MtuEzEUBmALgWgoLHgB5AUgdTHF48t4ZhlFvSBVbaFhbZ34Qh1mxsF2qua9eA6eqS4TFRasbMvfOTrnR-htTY5rQutP66FriSSEPUOzWlBS8Zbw52hGCKUVbSg7QK9SWpMiaspeooNSRbuGNTPkf__CVxsfvMFz5_zo8w7DaPCN7a3O_u7xHRzm1fnOxHC_q1g12Hxbbn40oQ9DiJtbP8KI5yP04fvWJvzV9pCtwTngS-hz_CPta_TCQZ_sm_15iL6dniwX59XF1dnnxfyiAlaTXDnOGm0tWxkQUjhd844z2TW0LOqINVaA5lJ3ltSrlWmppG2nwZmGAyetBHaIPk59NzH8LONkNfikbd_DaMM2qaaTrCWUFHg0QR1DStE6tYl-gLhTNVGPuaqnXIt9t2-6XQ3W_COnIAt4vweQNPQuwqh9-utaLoToCqsm5lO290_fEH-oRjIp1PL6Rn2RZ5di0Z2qZfEfJg86qXXYxhJy-s98D4pdm-I</recordid><startdate>19990506</startdate><enddate>19990506</enddate><creator>Coop, Andrew</creator><creator>Rothman, Richard B</creator><creator>Dersch, Christina</creator><creator>Partilla, John</creator><creator>Porreca, Frank</creator><creator>Davis, Peg</creator><creator>Jacobson, Arthur E</creator><creator>Rice, Kenner C</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>19990506</creationdate><title>δ Opioid Affinity and Selectivity of 4-Hydroxy-3-methoxyindolomorphinan Analogues Related to Naltrindole</title><author>Coop, Andrew ; Rothman, Richard B ; Dersch, Christina ; Partilla, John ; Porreca, Frank ; Davis, Peg ; Jacobson, Arthur E ; Rice, Kenner C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a310t-f436cee3bda575fc149437962021f0ede5ac47c9e01bbd827289cafd64a4087a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>Guanosine 5'-O-(3-Thiotriphosphate) - metabolism</topic><topic>Ileum - drug effects</topic><topic>Ileum - physiology</topic><topic>In Vitro Techniques</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Ligands</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Muscle Contraction - drug effects</topic><topic>Muscle, Smooth - drug effects</topic><topic>Muscle, Smooth - physiology</topic><topic>Naltrexone - analogs & derivatives</topic><topic>Naltrexone - chemical synthesis</topic><topic>Naltrexone - chemistry</topic><topic>Naltrexone - pharmacology</topic><topic>Narcotic Antagonists - chemical synthesis</topic><topic>Narcotic Antagonists - chemistry</topic><topic>Narcotic Antagonists - pharmacology</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>Rabbits</topic><topic>Receptors, Opioid, delta - antagonists & inhibitors</topic><topic>Receptors, Opioid, delta - metabolism</topic><topic>Vas Deferens - drug effects</topic><topic>Vas Deferens - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coop, Andrew</creatorcontrib><creatorcontrib>Rothman, Richard B</creatorcontrib><creatorcontrib>Dersch, Christina</creatorcontrib><creatorcontrib>Partilla, John</creatorcontrib><creatorcontrib>Porreca, Frank</creatorcontrib><creatorcontrib>Davis, Peg</creatorcontrib><creatorcontrib>Jacobson, Arthur E</creatorcontrib><creatorcontrib>Rice, Kenner C</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>Coop, Andrew</au><au>Rothman, Richard B</au><au>Dersch, Christina</au><au>Partilla, John</au><au>Porreca, Frank</au><au>Davis, Peg</au><au>Jacobson, Arthur E</au><au>Rice, Kenner C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>δ Opioid Affinity and Selectivity of 4-Hydroxy-3-methoxyindolomorphinan Analogues Related to Naltrindole</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1999-05-06</date><risdate>1999</risdate><volume>42</volume><issue>9</issue><spage>1673</spage><epage>1679</epage><pages>1673-1679</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2‘,3‘-indolomorphinan (13) was an exception, displaying excellent δ binding selectivity (δ K i = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-γ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>10229636</pmid><doi>10.1021/jm9807003</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1999-05, Vol.42 (9), p.1673-1679 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_69738020 |
| source | MEDLINE; ACS Publications |
| subjects | Animals Binding, Competitive Biological and medical sciences Brain - metabolism Guanosine 5'-O-(3-Thiotriphosphate) - metabolism Ileum - drug effects Ileum - physiology In Vitro Techniques Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Ligands Male Medical sciences Mice Mice, Inbred ICR Muscle Contraction - drug effects Muscle, Smooth - drug effects Muscle, Smooth - physiology Naltrexone - analogs & derivatives Naltrexone - chemical synthesis Naltrexone - chemistry Naltrexone - pharmacology Narcotic Antagonists - chemical synthesis Narcotic Antagonists - chemistry Narcotic Antagonists - pharmacology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Rabbits Receptors, Opioid, delta - antagonists & inhibitors Receptors, Opioid, delta - metabolism Vas Deferens - drug effects Vas Deferens - physiology |
| title | δ Opioid Affinity and Selectivity of 4-Hydroxy-3-methoxyindolomorphinan Analogues Related to Naltrindole |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T19%3A23%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=%CE%B4%20Opioid%20Affinity%20and%20Selectivity%20of%204-Hydroxy-3-methoxyindolomorphinan%20Analogues%20Related%20to%20Naltrindole&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Coop,%20Andrew&rft.date=1999-05-06&rft.volume=42&rft.issue=9&rft.spage=1673&rft.epage=1679&rft.pages=1673-1679&rft.issn=0022-2623&rft.eissn=1520-4804&rft.coden=JMCMAR&rft_id=info:doi/10.1021/jm9807003&rft_dat=%3Cproquest_cross%3E69738020%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=69738020&rft_id=info:pmid/10229636&rfr_iscdi=true |