C1‘-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols
In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1‘-position of the C3-alkyl side chain, a key pharmacophoric feature in this class...
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| Veröffentlicht in: | Journal of medicinal chemistry 2007-08, Vol.50 (17), p.4048-4060 |
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| container_title | Journal of medicinal chemistry |
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| creator | Papahatjis, Demetris P Nahmias, Victoria R Nikas, Spyros P Andreou, Thanos Alapafuja, Shakiru O Tsotinis, Andrew Guo, Jianxin Fan, Pusheng Makriyannis, Alexandros |
| description | In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1‘-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1‘-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1‘-cyclopropyl and C1‘-cyclopentyl groups are optimal pharmacophores for both receptors while the C1‘-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1‘-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2‘−C3‘ cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs. |
| doi_str_mv | 10.1021/jm070121a |
| format | Article |
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This putative subsite corresponds to substituents on the C1‘-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1‘-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1‘-cyclopropyl and C1‘-cyclopentyl groups are optimal pharmacophores for both receptors while the C1‘-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1‘-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2‘−C3‘ cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm070121a</identifier><identifier>PMID: 17672444</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Benzopyrans - chemical synthesis ; Benzopyrans - chemistry ; Benzopyrans - pharmacology ; Binding Sites ; Biological and medical sciences ; Cyclobutanes - chemical synthesis ; Cyclobutanes - chemistry ; Cyclobutanes - pharmacology ; Dronabinol - analogs & derivatives ; Dronabinol - chemical synthesis ; Dronabinol - pharmacology ; In Vitro Techniques ; Medical sciences ; Miscellaneous ; Models, Molecular ; Molecular Conformation ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Prosencephalon - metabolism ; Radioligand Assay ; Rats ; Receptor, Cannabinoid, CB1 - metabolism ; Receptor, Cannabinoid, CB2 - metabolism ; Stereoisomerism ; Structure-Activity Relationship ; Synaptosomes - metabolism</subject><ispartof>Journal of medicinal chemistry, 2007-08, Vol.50 (17), p.4048-4060</ispartof><rights>Copyright © 2007 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a478t-fce206522cb730fb9b9e1ddaf16b162e96f98f1a755a2fef350f93426b78abc43</citedby><cites>FETCH-LOGICAL-a478t-fce206522cb730fb9b9e1ddaf16b162e96f98f1a755a2fef350f93426b78abc43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm070121a$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm070121a$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19018815$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17672444$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Papahatjis, Demetris P</creatorcontrib><creatorcontrib>Nahmias, Victoria R</creatorcontrib><creatorcontrib>Nikas, Spyros P</creatorcontrib><creatorcontrib>Andreou, Thanos</creatorcontrib><creatorcontrib>Alapafuja, Shakiru O</creatorcontrib><creatorcontrib>Tsotinis, Andrew</creatorcontrib><creatorcontrib>Guo, Jianxin</creatorcontrib><creatorcontrib>Fan, Pusheng</creatorcontrib><creatorcontrib>Makriyannis, Alexandros</creatorcontrib><title>C1‘-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1‘-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1‘-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1‘-cyclopropyl and C1‘-cyclopentyl groups are optimal pharmacophores for both receptors while the C1‘-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1‘-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2‘−C3‘ cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs.</description><subject>Animals</subject><subject>Benzopyrans - chemical synthesis</subject><subject>Benzopyrans - chemistry</subject><subject>Benzopyrans - pharmacology</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cyclobutanes - chemical synthesis</subject><subject>Cyclobutanes - chemistry</subject><subject>Cyclobutanes - pharmacology</subject><subject>Dronabinol - analogs & derivatives</subject><subject>Dronabinol - chemical synthesis</subject><subject>Dronabinol - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Prosencephalon - metabolism</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Receptor, Cannabinoid, CB1 - metabolism</subject><subject>Receptor, Cannabinoid, CB2 - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Synaptosomes - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0MFq20AQBuCltDRukkNeIPjSQg9qZkbSrnRsReMWAg2xQ47LaLWL5Uhad9eG-pbHyPP1SapiE18KPQ3MfPwMvxAXCJ8QCK9WPShAQn4lJpgTJFkB2WsxASBKSFJ6It7FuAKAFCl9K05QSUVZlk3Elwp_Pz0n1c50nrvHXTedt42dVktuh-ntkkPPxq-XPtjpuFjYTeDlrgne8DBw3Q6-i2fijeMu2vPDPBX3118X1bfk5sfse_X5JuFMFZvEGUsgcyJTqxRcXdalxaZhh7JGSbaUriwcsspzJmddmoMr04xkrQquTZaeig_73HXwP7c2bnTfRmO7jgfrt1HLAhXkpP4LsVSKoMARftxDE3yMwTq9Dm3PYacR9N9m9Uuzo708hG7r3jZHeahyBO8PgKPhzgUeTBuPrgQsCsxHl-xdGzf218udw6OWKlW5XtzO9exhNoe5vNPXx1w2Ua_8Ngxjyf948A9lb5uW</recordid><startdate>20070823</startdate><enddate>20070823</enddate><creator>Papahatjis, Demetris P</creator><creator>Nahmias, Victoria R</creator><creator>Nikas, Spyros P</creator><creator>Andreou, Thanos</creator><creator>Alapafuja, Shakiru O</creator><creator>Tsotinis, Andrew</creator><creator>Guo, Jianxin</creator><creator>Fan, Pusheng</creator><creator>Makriyannis, Alexandros</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>7TK</scope><scope>7X8</scope></search><sort><creationdate>20070823</creationdate><title>C1‘-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols</title><author>Papahatjis, Demetris P ; Nahmias, Victoria R ; Nikas, Spyros P ; Andreou, Thanos ; Alapafuja, Shakiru O ; Tsotinis, Andrew ; Guo, Jianxin ; Fan, Pusheng ; Makriyannis, Alexandros</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a478t-fce206522cb730fb9b9e1ddaf16b162e96f98f1a755a2fef350f93426b78abc43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Benzopyrans - chemical synthesis</topic><topic>Benzopyrans - chemistry</topic><topic>Benzopyrans - pharmacology</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cyclobutanes - chemical synthesis</topic><topic>Cyclobutanes - chemistry</topic><topic>Cyclobutanes - pharmacology</topic><topic>Dronabinol - analogs & derivatives</topic><topic>Dronabinol - chemical synthesis</topic><topic>Dronabinol - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Prosencephalon - metabolism</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Receptor, Cannabinoid, CB1 - metabolism</topic><topic>Receptor, Cannabinoid, CB2 - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Synaptosomes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Papahatjis, Demetris P</creatorcontrib><creatorcontrib>Nahmias, Victoria R</creatorcontrib><creatorcontrib>Nikas, Spyros P</creatorcontrib><creatorcontrib>Andreou, Thanos</creatorcontrib><creatorcontrib>Alapafuja, Shakiru O</creatorcontrib><creatorcontrib>Tsotinis, Andrew</creatorcontrib><creatorcontrib>Guo, Jianxin</creatorcontrib><creatorcontrib>Fan, Pusheng</creatorcontrib><creatorcontrib>Makriyannis, Alexandros</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>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Papahatjis, Demetris P</au><au>Nahmias, Victoria R</au><au>Nikas, Spyros P</au><au>Andreou, Thanos</au><au>Alapafuja, Shakiru O</au><au>Tsotinis, Andrew</au><au>Guo, Jianxin</au><au>Fan, Pusheng</au><au>Makriyannis, Alexandros</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>C1‘-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2007-08-23</date><risdate>2007</risdate><volume>50</volume><issue>17</issue><spage>4048</spage><epage>4060</epage><pages>4048-4060</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1‘-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1‘-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1‘-cyclopropyl and C1‘-cyclopentyl groups are optimal pharmacophores for both receptors while the C1‘-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1‘-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2‘−C3‘ cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17672444</pmid><doi>10.1021/jm070121a</doi><tpages>13</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2007-08, Vol.50 (17), p.4048-4060 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Benzopyrans - chemical synthesis Benzopyrans - chemistry Benzopyrans - pharmacology Binding Sites Biological and medical sciences Cyclobutanes - chemical synthesis Cyclobutanes - chemistry Cyclobutanes - pharmacology Dronabinol - analogs & derivatives Dronabinol - chemical synthesis Dronabinol - pharmacology In Vitro Techniques Medical sciences Miscellaneous Models, Molecular Molecular Conformation Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Prosencephalon - metabolism Radioligand Assay Rats Receptor, Cannabinoid, CB1 - metabolism Receptor, Cannabinoid, CB2 - metabolism Stereoisomerism Structure-Activity Relationship Synaptosomes - metabolism |
| title | C1‘-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols |
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