Effects of Chemical Modification of Ursodeoxycholic Acid on TGR5 Activation
The aim of this study is to examine the ability of the bile acid analogues obtained by chemical modification of ursodeoxycholic acid (UDCA) for TGR5 activation. Eleven UDCA analogues including 3- or 7-methylated UDCAs and amino acid conjugates were investigated as to their ability to activate TGR5 b...
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Veröffentlicht in: | Biological & Pharmaceutical Bulletin 2011/01/01, Vol.34(1), pp.1-7 |
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creator | Iguchi, Yusuke Nishimaki-Mogami, Tomoko Yamaguchi, Masafumi Teraoka, Fumiteru Kaneko, Tetsuo Une, Mizuho |
description | The aim of this study is to examine the ability of the bile acid analogues obtained by chemical modification of ursodeoxycholic acid (UDCA) for TGR5 activation. Eleven UDCA analogues including 3- or 7-methylated UDCAs and amino acid conjugates were investigated as to their ability to activate TGR5 by means of the luciferase assay. It was noteworthy that 7α-methylated UDCA, namely 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid, had a significantly high affinity for and ability to activate TGR5 as compared to UDCA. Additionally, FXR activation ability of 7α-methylated UDCA was low relative to that of UDCA. However, other modification of UDCA, such as the introduction of methyl group at its C-3 position and oxidation or epimerization of hydroxyl group in the C-3 position, could not elicit such remarkable effect. The present findings would provide a useful strategy for the development of TGR5-selective agonist. |
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Eleven UDCA analogues including 3- or 7-methylated UDCAs and amino acid conjugates were investigated as to their ability to activate TGR5 by means of the luciferase assay. It was noteworthy that 7α-methylated UDCA, namely 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid, had a significantly high affinity for and ability to activate TGR5 as compared to UDCA. Additionally, FXR activation ability of 7α-methylated UDCA was low relative to that of UDCA. However, other modification of UDCA, such as the introduction of methyl group at its C-3 position and oxidation or epimerization of hydroxyl group in the C-3 position, could not elicit such remarkable effect. The present findings would provide a useful strategy for the development of TGR5-selective agonist.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.34.1</identifier><identifier>PMID: 21212509</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Dose-Response Relationship, Drug ; farnesoid X receptor ; Gene Expression Regulation - drug effects ; HEK293 Cells ; Humans ; metabolic syndrome ; Molecular Structure ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Structure-Activity Relationship ; TGR5 ; ursodeoxycholic acid ; Ursodeoxycholic Acid - analogs & derivatives ; Ursodeoxycholic Acid - chemistry ; Ursodeoxycholic Acid - pharmacology</subject><ispartof>Biological and Pharmaceutical Bulletin, 2011/01/01, Vol.34(1), pp.1-7</ispartof><rights>2011 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c679t-b8f0a1428787bf6434b03d14317ec706ede89eb85bf23d4ffead871b569a89f93</citedby><cites>FETCH-LOGICAL-c679t-b8f0a1428787bf6434b03d14317ec706ede89eb85bf23d4ffead871b569a89f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,4010,27900,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21212509$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Iguchi, Yusuke</creatorcontrib><creatorcontrib>Nishimaki-Mogami, Tomoko</creatorcontrib><creatorcontrib>Yamaguchi, Masafumi</creatorcontrib><creatorcontrib>Teraoka, Fumiteru</creatorcontrib><creatorcontrib>Kaneko, Tetsuo</creatorcontrib><creatorcontrib>Une, Mizuho</creatorcontrib><creatorcontrib>National Institute of Health Sciences</creatorcontrib><creatorcontrib>aFaculty of Pharmaceutical Science</creatorcontrib><creatorcontrib>Hiroshima International University</creatorcontrib><creatorcontrib>bDivision of Functional Biochemistry and Genomics</creatorcontrib><title>Effects of Chemical Modification of Ursodeoxycholic Acid on TGR5 Activation</title><title>Biological & Pharmaceutical Bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>The aim of this study is to examine the ability of the bile acid analogues obtained by chemical modification of ursodeoxycholic acid (UDCA) for TGR5 activation. Eleven UDCA analogues including 3- or 7-methylated UDCAs and amino acid conjugates were investigated as to their ability to activate TGR5 by means of the luciferase assay. It was noteworthy that 7α-methylated UDCA, namely 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid, had a significantly high affinity for and ability to activate TGR5 as compared to UDCA. Additionally, FXR activation ability of 7α-methylated UDCA was low relative to that of UDCA. However, other modification of UDCA, such as the introduction of methyl group at its C-3 position and oxidation or epimerization of hydroxyl group in the C-3 position, could not elicit such remarkable effect. The present findings would provide a useful strategy for the development of TGR5-selective agonist.</description><subject>Dose-Response Relationship, Drug</subject><subject>farnesoid X receptor</subject><subject>Gene Expression Regulation - drug effects</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>metabolic syndrome</subject><subject>Molecular Structure</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>TGR5</subject><subject>ursodeoxycholic acid</subject><subject>Ursodeoxycholic Acid - analogs & derivatives</subject><subject>Ursodeoxycholic Acid - chemistry</subject><subject>Ursodeoxycholic Acid - pharmacology</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkFFvFCEQx4mpsWc18ROYTfqgL3sywC7w0IfLpZ7GmiZN-0yABY_L3nKFPWO_vaxbz8QQZoD55T_DH6F3gJdAmPhkDmZJ2RJeoAVQxuuGQHOGFliCqFtoxDl6nfMOY8wxoa_QOYGyGiwX6Nu1986OuYq-Wm_dPljdV99jF3w5jSEOU-Eh5di5-OvJbmMfbLWyoatK6X5z15TLGH7-Qd-gl1732b19zhfo4fP1_fpLfXO7-bpe3dS25XKsjfBYAyOCC258yygzmHbAKHBnOW5d54R0RjTGE9qxMp_uBAfTtFIL6SW9QB9m3UOKj0eXR7UP2bq-14OLx6wEIRKz8u1CXv5H7uIxDWU4BYxJygVwXKiPM2VTzDk5rw4p7HV6UoDV5K8q_irKFBT0_bPg0exddwL_GlqAzQyU6uRlHPowuH9tbeYmxD4qggEUxpThKU17DhyopJRPSlez0i6P-oc7tdJpDLZ3p5nmAKd3u9VJuYH-BoD1oJ0</recordid><startdate>20110101</startdate><enddate>20110101</enddate><creator>Iguchi, Yusuke</creator><creator>Nishimaki-Mogami, Tomoko</creator><creator>Yamaguchi, Masafumi</creator><creator>Teraoka, Fumiteru</creator><creator>Kaneko, Tetsuo</creator><creator>Une, Mizuho</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20110101</creationdate><title>Effects of Chemical Modification of Ursodeoxycholic Acid on TGR5 Activation</title><author>Iguchi, Yusuke ; Nishimaki-Mogami, Tomoko ; Yamaguchi, Masafumi ; Teraoka, Fumiteru ; Kaneko, Tetsuo ; Une, Mizuho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c679t-b8f0a1428787bf6434b03d14317ec706ede89eb85bf23d4ffead871b569a89f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Dose-Response Relationship, Drug</topic><topic>farnesoid X receptor</topic><topic>Gene Expression Regulation - drug effects</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>metabolic syndrome</topic><topic>Molecular Structure</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>TGR5</topic><topic>ursodeoxycholic acid</topic><topic>Ursodeoxycholic Acid - analogs & derivatives</topic><topic>Ursodeoxycholic Acid - chemistry</topic><topic>Ursodeoxycholic Acid - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iguchi, Yusuke</creatorcontrib><creatorcontrib>Nishimaki-Mogami, Tomoko</creatorcontrib><creatorcontrib>Yamaguchi, Masafumi</creatorcontrib><creatorcontrib>Teraoka, Fumiteru</creatorcontrib><creatorcontrib>Kaneko, Tetsuo</creatorcontrib><creatorcontrib>Une, Mizuho</creatorcontrib><creatorcontrib>National Institute of Health Sciences</creatorcontrib><creatorcontrib>aFaculty of Pharmaceutical Science</creatorcontrib><creatorcontrib>Hiroshima International University</creatorcontrib><creatorcontrib>bDivision of Functional Biochemistry and Genomics</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & Pharmaceutical Bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iguchi, Yusuke</au><au>Nishimaki-Mogami, Tomoko</au><au>Yamaguchi, Masafumi</au><au>Teraoka, Fumiteru</au><au>Kaneko, Tetsuo</au><au>Une, Mizuho</au><aucorp>National Institute of Health Sciences</aucorp><aucorp>aFaculty of Pharmaceutical Science</aucorp><aucorp>Hiroshima International University</aucorp><aucorp>bDivision of Functional Biochemistry and Genomics</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Chemical Modification of Ursodeoxycholic Acid on TGR5 Activation</atitle><jtitle>Biological & Pharmaceutical Bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2011-01-01</date><risdate>2011</risdate><volume>34</volume><issue>1</issue><spage>1</spage><epage>7</epage><pages>1-7</pages><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>The aim of this study is to examine the ability of the bile acid analogues obtained by chemical modification of ursodeoxycholic acid (UDCA) for TGR5 activation. Eleven UDCA analogues including 3- or 7-methylated UDCAs and amino acid conjugates were investigated as to their ability to activate TGR5 by means of the luciferase assay. It was noteworthy that 7α-methylated UDCA, namely 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid, had a significantly high affinity for and ability to activate TGR5 as compared to UDCA. Additionally, FXR activation ability of 7α-methylated UDCA was low relative to that of UDCA. However, other modification of UDCA, such as the introduction of methyl group at its C-3 position and oxidation or epimerization of hydroxyl group in the C-3 position, could not elicit such remarkable effect. The present findings would provide a useful strategy for the development of TGR5-selective agonist.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>21212509</pmid><doi>10.1248/bpb.34.1</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Dose-Response Relationship, Drug farnesoid X receptor Gene Expression Regulation - drug effects HEK293 Cells Humans metabolic syndrome Molecular Structure Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Structure-Activity Relationship TGR5 ursodeoxycholic acid Ursodeoxycholic Acid - analogs & derivatives Ursodeoxycholic Acid - chemistry Ursodeoxycholic Acid - pharmacology |
title | Effects of Chemical Modification of Ursodeoxycholic Acid on TGR5 Activation |
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