C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics
Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain nove...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2017/10/01, Vol.65(10), pp.920-929 |
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| creator | Ishikawa, Kyoko Karaki, Fumika Tayama, Kaoru Higashi, Eika Hirayama, Shigeto Itoh, Kennosuke Fujii, Hideaki |
| description | Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the μ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties. |
| doi_str_mv | 10.1248/cpb.c17-00385 |
| format | Article |
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Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the μ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.c17-00385</identifier><identifier>PMID: 28966276</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Analgesics ; Analgesics, Opioid - chemical synthesis ; Analgesics, Opioid - chemistry ; Animals ; Buprenorphine ; Buprenorphine - analogs & derivatives ; Buprenorphine - chemistry ; C-homomorphinan ; CHO Cells ; Cricetinae ; Cricetulus ; Cyclization ; Derivatives ; Humans ; Kinetics ; Lead compounds ; Molecular Conformation ; Morphinans - chemical synthesis ; Morphinans - chemistry ; Narcotics ; opioid ; Opioid receptors ; Pain ; Pain perception ; Pharmacology ; Protein Binding ; Receptor mechanisms ; Receptors ; Receptors, Opioid - chemistry ; Receptors, Opioid - genetics ; Receptors, Opioid - metabolism ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - chemistry ; Recombinant Proteins - isolation & purification</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2017/10/01, Vol.65(10), pp.920-929</ispartof><rights>2017 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c729t-9d36aa963860cafbdc20b8e98326832d03b050530e3529b8cdc82eabf174254d3</citedby><cites>FETCH-LOGICAL-c729t-9d36aa963860cafbdc20b8e98326832d03b050530e3529b8cdc82eabf174254d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,1879,4012,27910,27911,27912</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28966276$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishikawa, Kyoko</creatorcontrib><creatorcontrib>Karaki, Fumika</creatorcontrib><creatorcontrib>Tayama, Kaoru</creatorcontrib><creatorcontrib>Higashi, Eika</creatorcontrib><creatorcontrib>Hirayama, Shigeto</creatorcontrib><creatorcontrib>Itoh, Kennosuke</creatorcontrib><creatorcontrib>Fujii, Hideaki</creatorcontrib><creatorcontrib>bMedicinal Research Laboratories</creatorcontrib><creatorcontrib>aLaboratory of Medicinal Chemistry</creatorcontrib><creatorcontrib>School of Pharmacy</creatorcontrib><creatorcontrib>Kitasato University</creatorcontrib><title>C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the μ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.</description><subject>Analgesics</subject><subject>Analgesics, Opioid - chemical synthesis</subject><subject>Analgesics, Opioid - chemistry</subject><subject>Animals</subject><subject>Buprenorphine</subject><subject>Buprenorphine - analogs & derivatives</subject><subject>Buprenorphine - chemistry</subject><subject>C-homomorphinan</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cyclization</subject><subject>Derivatives</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Lead compounds</subject><subject>Molecular Conformation</subject><subject>Morphinans - chemical synthesis</subject><subject>Morphinans - chemistry</subject><subject>Narcotics</subject><subject>opioid</subject><subject>Opioid receptors</subject><subject>Pain</subject><subject>Pain perception</subject><subject>Pharmacology</subject><subject>Protein Binding</subject><subject>Receptor mechanisms</subject><subject>Receptors</subject><subject>Receptors, Opioid - chemistry</subject><subject>Receptors, Opioid - genetics</subject><subject>Receptors, Opioid - metabolism</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - isolation & purification</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkEFv1DAQhS0EotvCkSuyxIVLytiOk_hYpdAiLeoBerYcZ9L1KnGCnVTqv8fZbbcSGnl8mE_vPT1CPjG4ZDyvvtmpubSszABEJd-QDRN5mUnOxVuyAQCVcVGIM3Ie4x6ASyjFe3LGK1UUvCw2xNbZ7TikCdPOeePpNQb3aGb3iJGaSLdoWlqPwzQuvo10HuldMxvn6W_TYaDGt_TXGJDWvfPOmr5_ovcRu6WnV970DxidjR_Iu870ET8-_xfk_sf3P_Vttr27-VlfbTNbcjVnqhWFMaoQVQHWdE1rOTQVqkrwIr0WRAMSpAAUkqumsq2tOJqmY2XOZd6KC_L1qDuF8e-CcdaDixb73ngcl6iZymXJKiXzhH75D92PS0iJD1Qpkg9UicqOlA1jjAE7PQU3mPCkGei1fZ3a16l9fWg_8Z-fVZdmwPZEv9SdgJsjkK5rW6NPteGrt42l3eHgNIeDaCGTEYDUoDisK03JFFujXR-V9nE2D3iyMmF2tsdDsEKuOdM-JXw970zQ6MU_eHStwQ</recordid><startdate>2017</startdate><enddate>2017</enddate><creator>Ishikawa, Kyoko</creator><creator>Karaki, Fumika</creator><creator>Tayama, Kaoru</creator><creator>Higashi, Eika</creator><creator>Hirayama, Shigeto</creator><creator>Itoh, Kennosuke</creator><creator>Fujii, Hideaki</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>2017</creationdate><title>C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics</title><author>Ishikawa, Kyoko ; Karaki, Fumika ; Tayama, Kaoru ; Higashi, Eika ; Hirayama, Shigeto ; Itoh, Kennosuke ; Fujii, Hideaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c729t-9d36aa963860cafbdc20b8e98326832d03b050530e3529b8cdc82eabf174254d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Analgesics</topic><topic>Analgesics, Opioid - chemical synthesis</topic><topic>Analgesics, Opioid - chemistry</topic><topic>Animals</topic><topic>Buprenorphine</topic><topic>Buprenorphine - analogs & derivatives</topic><topic>Buprenorphine - chemistry</topic><topic>C-homomorphinan</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cyclization</topic><topic>Derivatives</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Lead compounds</topic><topic>Molecular Conformation</topic><topic>Morphinans - chemical synthesis</topic><topic>Morphinans - chemistry</topic><topic>Narcotics</topic><topic>opioid</topic><topic>Opioid receptors</topic><topic>Pain</topic><topic>Pain perception</topic><topic>Pharmacology</topic><topic>Protein Binding</topic><topic>Receptor mechanisms</topic><topic>Receptors</topic><topic>Receptors, Opioid - chemistry</topic><topic>Receptors, Opioid - genetics</topic><topic>Receptors, Opioid - metabolism</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - isolation & purification</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishikawa, Kyoko</creatorcontrib><creatorcontrib>Karaki, Fumika</creatorcontrib><creatorcontrib>Tayama, Kaoru</creatorcontrib><creatorcontrib>Higashi, Eika</creatorcontrib><creatorcontrib>Hirayama, Shigeto</creatorcontrib><creatorcontrib>Itoh, Kennosuke</creatorcontrib><creatorcontrib>Fujii, Hideaki</creatorcontrib><creatorcontrib>bMedicinal Research Laboratories</creatorcontrib><creatorcontrib>aLaboratory of Medicinal Chemistry</creatorcontrib><creatorcontrib>School of Pharmacy</creatorcontrib><creatorcontrib>Kitasato University</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishikawa, Kyoko</au><au>Karaki, Fumika</au><au>Tayama, Kaoru</au><au>Higashi, Eika</au><au>Hirayama, Shigeto</au><au>Itoh, Kennosuke</au><au>Fujii, Hideaki</au><aucorp>bMedicinal Research Laboratories</aucorp><aucorp>aLaboratory of Medicinal Chemistry</aucorp><aucorp>School of Pharmacy</aucorp><aucorp>Kitasato University</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2017</date><risdate>2017</risdate><volume>65</volume><issue>10</issue><spage>920</spage><epage>929</epage><pages>920-929</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the μ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>28966276</pmid><doi>10.1248/cpb.c17-00385</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Analgesics Analgesics, Opioid - chemical synthesis Analgesics, Opioid - chemistry Animals Buprenorphine Buprenorphine - analogs & derivatives Buprenorphine - chemistry C-homomorphinan CHO Cells Cricetinae Cricetulus Cyclization Derivatives Humans Kinetics Lead compounds Molecular Conformation Morphinans - chemical synthesis Morphinans - chemistry Narcotics opioid Opioid receptors Pain Pain perception Pharmacology Protein Binding Receptor mechanisms Receptors Receptors, Opioid - chemistry Receptors, Opioid - genetics Receptors, Opioid - metabolism Recombinant Proteins - biosynthesis Recombinant Proteins - chemistry Recombinant Proteins - isolation & purification |
| title | C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics |
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