Nonequilibrium opioid antagonist activity of 6,14-dideoxynaltrexone derivatives
A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3-5 of the series possessed irreversible antagonist activity pr...
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| Veröffentlicht in: | Journal of medicinal chemistry 1987-06, Vol.30 (6), p.1040-1044 |
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| container_end_page | 1044 |
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| container_issue | 6 |
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| container_title | Journal of medicinal chemistry |
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| creator | Schoenecker, J. W Takemori, A. E Portoghese, P. S |
| description | A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3-5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-beta-funaltrexamine (14-deoxy-beta-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of beta-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile. |
| doi_str_mv | 10.1021/jm00389a014 |
| format | Article |
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W</creatorcontrib><creatorcontrib>Takemori, A. E</creatorcontrib><creatorcontrib>Portoghese, P. S</creatorcontrib><title>Nonequilibrium opioid antagonist activity of 6,14-dideoxynaltrexone derivatives</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3-5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-beta-funaltrexamine (14-deoxy-beta-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of beta-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.</description><subject>Animals</subject><subject>Chemistry</subject><subject>Cyclazocine - analogs & derivatives</subject><subject>Cyclazocine - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enkephalin, Leucine - analogs & derivatives</subject><subject>Enkephalin, Leucine - pharmacology</subject><subject>Enkephalin, Leucine-2-Alanine</subject><subject>Ethylketocyclazocine</subject><subject>Exact sciences and technology</subject><subject>Guinea Pigs</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms</subject><subject>Mice</subject><subject>Naltrexone - analogs & derivatives</subject><subject>Narcotic Antagonists - chemical synthesis</subject><subject>Narcotic Antagonists - pharmacology</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Receptors, Opioid - drug effects</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1987</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0EtvEzEUBWCrApW0ZcUaaRaILsqU67e7rCLaIqUPoBVLy7E9yGFmnNozVfLvcZQoYtGVF-e7R9ZB6AOGcwwEf110AFRdGMDsAE0wJ1AzBewNmgAQUhNB6Dt0lPMCisOEHqJDCpRjKSfo_i72_nkMbZinMHZVXIYYXGX6wfyJfchDZewQXsKwrmJTiS-Y1S44H1fr3rRD8qtyXjmfwospzOcT9LYxbfbvd-8xerr69ji9qWf319-nl7PaUEWHmoPDBEvOGw62AWCAvXNcWImFwBdSWEaUZ0paqzx1aq54g6UhDBOubCPoMfq87V2m-Dz6POguZOvb1vQ-jlnL0k2F3MCzLbQp5px8o5cpdCatNQa9mU__N1_RH3e147zzbm93e5X80y432Zq2Saa3Ie-ZogxTtWH1lpUB_Wofm_RXC0kl148Pv7SE2e_pzx8zfVv86dYbm_UijqmMm1_94D-IJpJb</recordid><startdate>19870601</startdate><enddate>19870601</enddate><creator>Schoenecker, J. W</creator><creator>Takemori, A. E</creator><creator>Portoghese, P. S</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>19870601</creationdate><title>Nonequilibrium opioid antagonist activity of 6,14-dideoxynaltrexone derivatives</title><author>Schoenecker, J. W ; Takemori, A. E ; Portoghese, P. S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-50d121755f50cf00401edd56c71661976c428e487cc8e3d8b85f17a241258cf63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1987</creationdate><topic>Animals</topic><topic>Chemistry</topic><topic>Cyclazocine - analogs & derivatives</topic><topic>Cyclazocine - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enkephalin, Leucine - analogs & derivatives</topic><topic>Enkephalin, Leucine - pharmacology</topic><topic>Enkephalin, Leucine-2-Alanine</topic><topic>Ethylketocyclazocine</topic><topic>Exact sciences and technology</topic><topic>Guinea Pigs</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms</topic><topic>Mice</topic><topic>Naltrexone - analogs & derivatives</topic><topic>Narcotic Antagonists - chemical synthesis</topic><topic>Narcotic Antagonists - pharmacology</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Receptors, Opioid - drug effects</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schoenecker, J. W</creatorcontrib><creatorcontrib>Takemori, A. E</creatorcontrib><creatorcontrib>Portoghese, P. S</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>Schoenecker, J. W</au><au>Takemori, A. E</au><au>Portoghese, P. S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nonequilibrium opioid antagonist activity of 6,14-dideoxynaltrexone derivatives</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1987-06-01</date><risdate>1987</risdate><volume>30</volume><issue>6</issue><spage>1040</spage><epage>1044</epage><pages>1040-1044</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3-5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-beta-funaltrexamine (14-deoxy-beta-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of beta-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>3035177</pmid><doi>10.1021/jm00389a014</doi><tpages>5</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1987-06, Vol.30 (6), p.1040-1044 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Chemistry Cyclazocine - analogs & derivatives Cyclazocine - pharmacology Dose-Response Relationship, Drug Enkephalin, Leucine - analogs & derivatives Enkephalin, Leucine - pharmacology Enkephalin, Leucine-2-Alanine Ethylketocyclazocine Exact sciences and technology Guinea Pigs Heterocyclic compounds Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms Mice Naltrexone - analogs & derivatives Narcotic Antagonists - chemical synthesis Narcotic Antagonists - pharmacology Organic chemistry Preparations and properties Receptors, Opioid - drug effects Structure-Activity Relationship |
| title | Nonequilibrium opioid antagonist activity of 6,14-dideoxynaltrexone derivatives |
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