Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain
We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the oth...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-04, Vol.22 (8), p.2775-2779 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Nagase, Hiroshi Akiyama, Junko Nakajima, Ryo Hirayama, Shigeto Nemoto, Toru Gouda, Hiroaki Hirono, Shuichi Fujii, Hideaki |
| description | We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives. |
| doi_str_mv | 10.1016/j.bmcl.2012.02.082 |
| format | Article |
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The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.02.082</identifier><identifier>PMID: 22460026</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>agonists ; Amides - chemistry ; Amides - pharmacology ; Analgesics, Opioid - chemical synthesis ; Analgesics, Opioid - chemistry ; Analgesics, Opioid - pharmacology ; Biological and medical sciences ; Bridged-Ring Compounds - chemistry ; Bridged-Ring Compounds - pharmacology ; chemical derivatives ; Lone electron pair ; Medical sciences ; Models, Molecular ; Molecular Structure ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Opioid ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; pharmacology ; Pharmacology. Drug treatments ; Propellane derivative ; Protein Binding - drug effects ; Receptors, Opioid, kappa - agonists ; Shielding effect</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-04, Vol.22 (8), p.2775-2779</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. 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Part 2: Propellane derivatives with an amide side chain</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.</description><subject>agonists</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>Analgesics, Opioid - chemical synthesis</subject><subject>Analgesics, Opioid - chemistry</subject><subject>Analgesics, Opioid - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bridged-Ring Compounds - chemistry</subject><subject>Bridged-Ring Compounds - pharmacology</subject><subject>chemical derivatives</subject><subject>Lone electron pair</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Opioid</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Propellane derivative</subject><subject>Protein Binding - drug effects</subject><subject>Receptors, Opioid, kappa - agonists</subject><subject>Shielding effect</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi0EotvCC3AAXxBcstgTx0kQF1TxT6pEpRaJm-XYk66XJA52dqt9iT4zjrLQA1Kl0czl930z9kfIC87WnHH5brtuetOtgXFYs1QVPCIrLqTIcsGKx2TFasmyqhY_T8hpjFvGuGBCPCUnAEIyBnJF7q4Ow7TB6CL1LR3wlvrReWepxeD2enJ7jPTWTRuq6Rj8iF2nB6TxF3Y4-YHqwdKkd4GOGx16bXznbw5reqnDROE9vbzX_O-Y5L2zyW1uZqPd8Iw8aXUX8flxnpHrz5-uz79mF9-_fDv_eJEZIWDKDHDAUlRQclYi5KKs84Y1RhospLBYt6aWRoBkra01yKbUNVSlrHJreG3zM_JmsU1P-r3DOKneRbPc6XdR1YmGqqplIt8-SHKWi4qXUMwoLKgJPsaArRqD63U4JEjNgamtmgNTc2CKpaogiV4e_XdNj_af5G9CCXh9BHQ0umuDHoyL91xRFUxCmbhXC9dqr_RNSMyPq7SpSKnnEmBe9WEhMH3s3mFQ0TgcDFoX0EzKevfQpX8AVwy-JQ</recordid><startdate>20120415</startdate><enddate>20120415</enddate><creator>Nagase, Hiroshi</creator><creator>Akiyama, Junko</creator><creator>Nakajima, Ryo</creator><creator>Hirayama, Shigeto</creator><creator>Nemoto, Toru</creator><creator>Gouda, Hiroaki</creator><creator>Hirono, Shuichi</creator><creator>Fujii, Hideaki</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20120415</creationdate><title>Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain</title><author>Nagase, Hiroshi ; Akiyama, Junko ; Nakajima, Ryo ; Hirayama, Shigeto ; Nemoto, Toru ; Gouda, Hiroaki ; Hirono, Shuichi ; Fujii, Hideaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-c212e74827107e234793b0bc6ce564de9fc96c4260fd9a26b7a9287683dc19d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>agonists</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Analgesics, Opioid - chemical synthesis</topic><topic>Analgesics, Opioid - chemistry</topic><topic>Analgesics, Opioid - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bridged-Ring Compounds - chemistry</topic><topic>Bridged-Ring Compounds - pharmacology</topic><topic>chemical derivatives</topic><topic>Lone electron pair</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Opioid</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Propellane derivative</topic><topic>Protein Binding - drug effects</topic><topic>Receptors, Opioid, kappa - agonists</topic><topic>Shielding effect</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nagase, Hiroshi</creatorcontrib><creatorcontrib>Akiyama, Junko</creatorcontrib><creatorcontrib>Nakajima, Ryo</creatorcontrib><creatorcontrib>Hirayama, Shigeto</creatorcontrib><creatorcontrib>Nemoto, Toru</creatorcontrib><creatorcontrib>Gouda, Hiroaki</creatorcontrib><creatorcontrib>Hirono, Shuichi</creatorcontrib><creatorcontrib>Fujii, Hideaki</creatorcontrib><collection>AGRIS</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nagase, Hiroshi</au><au>Akiyama, Junko</au><au>Nakajima, Ryo</au><au>Hirayama, Shigeto</au><au>Nemoto, Toru</au><au>Gouda, Hiroaki</au><au>Hirono, Shuichi</au><au>Fujii, Hideaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-04-15</date><risdate>2012</risdate><volume>22</volume><issue>8</issue><spage>2775</spage><epage>2779</epage><pages>2775-2779</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22460026</pmid><doi>10.1016/j.bmcl.2012.02.082</doi><tpages>5</tpages></addata></record> |
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| subjects | agonists Amides - chemistry Amides - pharmacology Analgesics, Opioid - chemical synthesis Analgesics, Opioid - chemistry Analgesics, Opioid - pharmacology Biological and medical sciences Bridged-Ring Compounds - chemistry Bridged-Ring Compounds - pharmacology chemical derivatives Lone electron pair Medical sciences Models, Molecular Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Opioid Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems pharmacology Pharmacology. Drug treatments Propellane derivative Protein Binding - drug effects Receptors, Opioid, kappa - agonists Shielding effect |
| title | Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain |
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