Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors
Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at...
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Veröffentlicht in: | Journal of medicinal chemistry 1989-08, Vol.32 (8), p.1873-1879 |
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container_issue | 8 |
container_start_page | 1873 |
container_title | Journal of medicinal chemistry |
container_volume | 32 |
creator | Jacobson, Kenneth A Kiriasis, Leonidas Barone, Suzanne Bradbury, Barton J Kammula, Udai Campagne, Jean Michel Daly, John W Neumeyer, John L Pfleiderer, Wolfgang Secunda, Sherrie |
description | Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [( 3H]-N6-(phenylisopropyl)adenosine as radioligand] or striatum [3H]-5'-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxy-methyl)oxyl] phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was greater than 740-fold A1 selective. |
doi_str_mv | 10.1021/jm00128a031 |
format | Article |
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Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [( 3H]-N6-(phenylisopropyl)adenosine as radioligand] or striatum [3H]-5'-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxy-methyl)oxyl] phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was greater than 740-fold A1 selective.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00128a031</identifier><identifier>PMID: 2754711</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Binding, Competitive ; Chemical Phenomena ; Chemistry ; Exact sciences and technology ; Heterocyclic compounds ; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives ; In Vitro Techniques ; Organic chemistry ; Preparations and properties ; Radioligand Assay ; Rats ; Receptors, Purinergic - drug effects ; Receptors, Purinergic - metabolism ; Structure-Activity Relationship ; Sulfur ; Xanthines - chemical synthesis ; Xanthines - metabolism ; Xanthines - pharmacology</subject><ispartof>Journal of medicinal chemistry, 1989-08, Vol.32 (8), p.1873-1879</ispartof><rights>1991 INIST-CNRS</rights><rights>1989 American Chemical Society 1989</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a474t-9a7bf85e0bcf1a47f9b675b0e0513b14e1df63e021e1e7c75efdb29326dc24db3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00128a031$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00128a031$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19476941$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2754711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jacobson, Kenneth A</creatorcontrib><creatorcontrib>Kiriasis, Leonidas</creatorcontrib><creatorcontrib>Barone, Suzanne</creatorcontrib><creatorcontrib>Bradbury, Barton J</creatorcontrib><creatorcontrib>Kammula, Udai</creatorcontrib><creatorcontrib>Campagne, Jean Michel</creatorcontrib><creatorcontrib>Daly, John W</creatorcontrib><creatorcontrib>Neumeyer, John L</creatorcontrib><creatorcontrib>Pfleiderer, Wolfgang</creatorcontrib><creatorcontrib>Secunda, Sherrie</creatorcontrib><title>Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [( 3H]-N6-(phenylisopropyl)adenosine as radioligand] or striatum [3H]-5'-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxy-methyl)oxyl] phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was greater than 740-fold A1 selective.</description><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives</subject><subject>In Vitro Techniques</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Receptors, Purinergic - drug effects</subject><subject>Receptors, Purinergic - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Sulfur</subject><subject>Xanthines - chemical synthesis</subject><subject>Xanthines - metabolism</subject><subject>Xanthines - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1989</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1v1DAQxS0EKkvhxBkpF9oDBPyVeHNBqiooSCsBauHAxZo4k623WXuxnVX739fRrpZW4mTZ7-c3M28Iec3oB0Y5-7haU8r4HKhgT8iMVZyWck7lUzKjlPOS11w8Jy9iXFGaES6OyBFXlVSMzUh3OQ79GErjXQLrrFsW7L0oOwvDzd1wCy5dW4dFh8FuIdktxgJiEXFAM92KDMDSOxtTFlJxxkro0Pk4fQpocJN8iC_Jsx6GiK_25zH59eXz1fnXcvH94tv52aIEqWQqG1BtP6-QtqZn-alv2lpVLUVaMdEyiazra4F5ZGSojKqw71reCF53hsuuFcfk0853M7Zr7Ay6FGDQm2DXEO60B6sfK85e66XfaiFVU1ciG5zsDYL_O2JMem2jwWEAh36MWjUsx9vMM_huB5rgYwzYH4owqqel6AdLyfSbh30d2P0Wsv52r0M0MPQBnLHxn2UjVd3IiSt3XI4bbw86hBtdK6EqffXjUi84-_mn_n2hp3FOdzyYqFd-DC6n_98O7wGLerK7</recordid><startdate>19890801</startdate><enddate>19890801</enddate><creator>Jacobson, Kenneth A</creator><creator>Kiriasis, Leonidas</creator><creator>Barone, Suzanne</creator><creator>Bradbury, Barton J</creator><creator>Kammula, Udai</creator><creator>Campagne, Jean Michel</creator><creator>Daly, John W</creator><creator>Neumeyer, John L</creator><creator>Pfleiderer, Wolfgang</creator><creator>Secunda, Sherrie</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><scope>5PM</scope></search><sort><creationdate>19890801</creationdate><title>Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors</title><author>Jacobson, Kenneth A ; Kiriasis, Leonidas ; Barone, Suzanne ; Bradbury, Barton J ; Kammula, Udai ; Campagne, Jean Michel ; Daly, John W ; Neumeyer, John L ; Pfleiderer, Wolfgang ; Secunda, Sherrie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a474t-9a7bf85e0bcf1a47f9b675b0e0513b14e1df63e021e1e7c75efdb29326dc24db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1989</creationdate><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives</topic><topic>In Vitro Techniques</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Receptors, Purinergic - drug effects</topic><topic>Receptors, Purinergic - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Sulfur</topic><topic>Xanthines - chemical synthesis</topic><topic>Xanthines - metabolism</topic><topic>Xanthines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jacobson, Kenneth A</creatorcontrib><creatorcontrib>Kiriasis, Leonidas</creatorcontrib><creatorcontrib>Barone, Suzanne</creatorcontrib><creatorcontrib>Bradbury, Barton J</creatorcontrib><creatorcontrib>Kammula, Udai</creatorcontrib><creatorcontrib>Campagne, Jean Michel</creatorcontrib><creatorcontrib>Daly, John W</creatorcontrib><creatorcontrib>Neumeyer, John L</creatorcontrib><creatorcontrib>Pfleiderer, Wolfgang</creatorcontrib><creatorcontrib>Secunda, Sherrie</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jacobson, Kenneth A</au><au>Kiriasis, Leonidas</au><au>Barone, Suzanne</au><au>Bradbury, Barton J</au><au>Kammula, Udai</au><au>Campagne, Jean Michel</au><au>Daly, John W</au><au>Neumeyer, John L</au><au>Pfleiderer, Wolfgang</au><au>Secunda, Sherrie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1989-08-01</date><risdate>1989</risdate><volume>32</volume><issue>8</issue><spage>1873</spage><epage>1879</epage><pages>1873-1879</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [( 3H]-N6-(phenylisopropyl)adenosine as radioligand] or striatum [3H]-5'-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxy-methyl)oxyl] phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was greater than 740-fold A1 selective.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>2754711</pmid><doi>10.1021/jm00128a031</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Binding, Competitive Chemical Phenomena Chemistry Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives In Vitro Techniques Organic chemistry Preparations and properties Radioligand Assay Rats Receptors, Purinergic - drug effects Receptors, Purinergic - metabolism Structure-Activity Relationship Sulfur Xanthines - chemical synthesis Xanthines - metabolism Xanthines - pharmacology |
title | Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors |
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