High Affinity Electrophilic and Photoactivatable Covalent Endocannabinoid Probes for the CB1 Receptor
We have designed and synthesized the first two high affinity covalent anandamide probes for the CB1 receptor by introducing either an electrophilic isothiocyanato or a photoactivatable azido group at the terminal carbon of the arachidonic acid moiety. The headgroup of these anandamide analogues was...
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| Veröffentlicht in: | Journal of medicinal chemistry 2005-10, Vol.48 (20), p.6423-6429 |
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| container_title | Journal of medicinal chemistry |
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| creator | Li, Chen Xu, Wei Vadivel, Subramanian K Fan, Pusheng Makriyannis, Alexandros |
| description | We have designed and synthesized the first two high affinity covalent anandamide probes for the CB1 receptor by introducing either an electrophilic isothiocyanato or a photoactivatable azido group at the terminal carbon of the arachidonic acid moiety. The headgroup of these anandamide analogues was optimized by using a cyclopropylamide substituent to impart optimal CB1 affinity. Both 20-isothiocyanato-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (1, AM3677) and 20-azido-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (2, AM3661) exhibited high selectivities for the CB1 receptor with K i values of 1.3 and 0.9 nM, respectively. Using suitable experimental conditions, both ligands were shown to covalently label the CB1 receptor with high efficiency. These two covalent probes for the endocannabinoid CB1 binding site open the door for exploring the ligand binding motifs involved in the activation of the CB1 receptor by its endogenous ligand, anandamide. |
| doi_str_mv | 10.1021/jm050272i |
| format | Article |
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The headgroup of these anandamide analogues was optimized by using a cyclopropylamide substituent to impart optimal CB1 affinity. Both 20-isothiocyanato-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (1, AM3677) and 20-azido-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (2, AM3661) exhibited high selectivities for the CB1 receptor with K i values of 1.3 and 0.9 nM, respectively. Using suitable experimental conditions, both ligands were shown to covalently label the CB1 receptor with high efficiency. These two covalent probes for the endocannabinoid CB1 binding site open the door for exploring the ligand binding motifs involved in the activation of the CB1 receptor by its endogenous ligand, anandamide.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm050272i</identifier><identifier>PMID: 16190768</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Arachidonic Acids - chemical synthesis ; Arachidonic Acids - metabolism ; Arachidonic Acids - radiation effects ; Azides - chemical synthesis ; Azides - metabolism ; Azides - radiation effects ; Binding Sites ; Biological and medical sciences ; Brain - metabolism ; Cannabinoid Receptor Modulators - metabolism ; Endocannabinoids ; In Vitro Techniques ; Isothiocyanates - chemical synthesis ; Isothiocyanates - metabolism ; Ligands ; Light ; Medical sciences ; Miscellaneous ; Molecular Probes - chemical synthesis ; Molecular Probes - metabolism ; Molecular Probes - radiation effects ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Polyunsaturated Alkamides ; Radioligand Assay ; Rats ; Receptor, Cannabinoid, CB1 - metabolism ; Stereoisomerism</subject><ispartof>Journal of medicinal chemistry, 2005-10, Vol.48 (20), p.6423-6429</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a412t-2034615de4c0eba83683d0fbad22f9f28ba2d3be352e63e93f6f237d4dc179c23</citedby><cites>FETCH-LOGICAL-a412t-2034615de4c0eba83683d0fbad22f9f28ba2d3be352e63e93f6f237d4dc179c23</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/jm050272i$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm050272i$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17165196$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16190768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Chen</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Vadivel, Subramanian K</creatorcontrib><creatorcontrib>Fan, Pusheng</creatorcontrib><creatorcontrib>Makriyannis, Alexandros</creatorcontrib><title>High Affinity Electrophilic and Photoactivatable Covalent Endocannabinoid Probes for the CB1 Receptor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We have designed and synthesized the first two high affinity covalent anandamide probes for the CB1 receptor by introducing either an electrophilic isothiocyanato or a photoactivatable azido group at the terminal carbon of the arachidonic acid moiety. The headgroup of these anandamide analogues was optimized by using a cyclopropylamide substituent to impart optimal CB1 affinity. Both 20-isothiocyanato-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (1, AM3677) and 20-azido-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (2, AM3661) exhibited high selectivities for the CB1 receptor with K i values of 1.3 and 0.9 nM, respectively. Using suitable experimental conditions, both ligands were shown to covalently label the CB1 receptor with high efficiency. These two covalent probes for the endocannabinoid CB1 binding site open the door for exploring the ligand binding motifs involved in the activation of the CB1 receptor by its endogenous ligand, anandamide.</description><subject>Animals</subject><subject>Arachidonic Acids - chemical synthesis</subject><subject>Arachidonic Acids - metabolism</subject><subject>Arachidonic Acids - radiation effects</subject><subject>Azides - chemical synthesis</subject><subject>Azides - metabolism</subject><subject>Azides - radiation effects</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Cannabinoid Receptor Modulators - metabolism</subject><subject>Endocannabinoids</subject><subject>In Vitro Techniques</subject><subject>Isothiocyanates - chemical synthesis</subject><subject>Isothiocyanates - metabolism</subject><subject>Ligands</subject><subject>Light</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Molecular Probes - chemical synthesis</subject><subject>Molecular Probes - metabolism</subject><subject>Molecular Probes - radiation effects</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Polyunsaturated Alkamides</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Receptor, Cannabinoid, CB1 - metabolism</subject><subject>Stereoisomerism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0MFuEzEQBmALgWhaOPACaC8gcViwx17v-thGoUVEUEER3Cyvd0wcNnawnYq-PVslai5InOYwn_4Z_YS8YPQto8DerTe0odCCf0RmrAFai46Kx2RGKUANEvgJOc15TSnlDPhTcsIkU7SV3Yzglf-5qs6d88GXu2oxoi0pbld-9LYyYaiuV7FEY4u_NcX0I1bzeGtGDKVahCFaE4LpfYh-kin2mCsXU1VWk7tg1Re0uC0xPSNPnBkzPj_MM_Lt_eJmflUvP19-mJ8vayMYlBooF5I1AwpLsTcdlx0fqOvNAOCUg643MPAeeQMoOSrupAPeDmKwrFUW-Bl5vc_dpvh7h7nojc8Wx9EEjLusZSeFEOr_kCmuBFA5wTd7aFPMOaHT2-Q3Jt1pRvV9-fqh_Mm-PITu-g0OR3loewKvDsBka0aXTLA-H13LZMPU_dF673wu-Odhb9IvLVveNvrm-qv-rj7--ARLodUx19is13GXwlTyPx78CziEp0M</recordid><startdate>20051006</startdate><enddate>20051006</enddate><creator>Li, Chen</creator><creator>Xu, Wei</creator><creator>Vadivel, Subramanian K</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>20051006</creationdate><title>High Affinity Electrophilic and Photoactivatable Covalent Endocannabinoid Probes for the CB1 Receptor</title><author>Li, Chen ; Xu, Wei ; Vadivel, Subramanian K ; Fan, Pusheng ; Makriyannis, Alexandros</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a412t-2034615de4c0eba83683d0fbad22f9f28ba2d3be352e63e93f6f237d4dc179c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Arachidonic Acids - chemical synthesis</topic><topic>Arachidonic Acids - metabolism</topic><topic>Arachidonic Acids - radiation effects</topic><topic>Azides - chemical synthesis</topic><topic>Azides - metabolism</topic><topic>Azides - radiation effects</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>Cannabinoid Receptor Modulators - metabolism</topic><topic>Endocannabinoids</topic><topic>In Vitro Techniques</topic><topic>Isothiocyanates - chemical synthesis</topic><topic>Isothiocyanates - metabolism</topic><topic>Ligands</topic><topic>Light</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Molecular Probes - chemical synthesis</topic><topic>Molecular Probes - metabolism</topic><topic>Molecular Probes - radiation effects</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Polyunsaturated Alkamides</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Receptor, Cannabinoid, CB1 - metabolism</topic><topic>Stereoisomerism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Chen</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Vadivel, Subramanian K</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>Li, Chen</au><au>Xu, Wei</au><au>Vadivel, Subramanian K</au><au>Fan, Pusheng</au><au>Makriyannis, Alexandros</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High Affinity Electrophilic and Photoactivatable Covalent Endocannabinoid Probes for the CB1 Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2005-10-06</date><risdate>2005</risdate><volume>48</volume><issue>20</issue><spage>6423</spage><epage>6429</epage><pages>6423-6429</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>We have designed and synthesized the first two high affinity covalent anandamide probes for the CB1 receptor by introducing either an electrophilic isothiocyanato or a photoactivatable azido group at the terminal carbon of the arachidonic acid moiety. The headgroup of these anandamide analogues was optimized by using a cyclopropylamide substituent to impart optimal CB1 affinity. Both 20-isothiocyanato-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (1, AM3677) and 20-azido-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (2, AM3661) exhibited high selectivities for the CB1 receptor with K i values of 1.3 and 0.9 nM, respectively. Using suitable experimental conditions, both ligands were shown to covalently label the CB1 receptor with high efficiency. These two covalent probes for the endocannabinoid CB1 binding site open the door for exploring the ligand binding motifs involved in the activation of the CB1 receptor by its endogenous ligand, anandamide.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16190768</pmid><doi>10.1021/jm050272i</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Arachidonic Acids - chemical synthesis Arachidonic Acids - metabolism Arachidonic Acids - radiation effects Azides - chemical synthesis Azides - metabolism Azides - radiation effects Binding Sites Biological and medical sciences Brain - metabolism Cannabinoid Receptor Modulators - metabolism Endocannabinoids In Vitro Techniques Isothiocyanates - chemical synthesis Isothiocyanates - metabolism Ligands Light Medical sciences Miscellaneous Molecular Probes - chemical synthesis Molecular Probes - metabolism Molecular Probes - radiation effects Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Polyunsaturated Alkamides Radioligand Assay Rats Receptor, Cannabinoid, CB1 - metabolism Stereoisomerism |
| title | High Affinity Electrophilic and Photoactivatable Covalent Endocannabinoid Probes for the CB1 Receptor |
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