Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK2) Receptors by Novel Bivalent Ligands
Both μ-opioid (MOP) and type 2 cholecystokinin (CCK2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2 receptors to determine w...
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-01, Vol.52 (2), p.247-258 |
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| creator | Zheng, Yaguo Akgün, Eyup Harikumar, Kaleeckal G Hopson, Jessika Powers, Michael D Lunzer, Mary M Miller, Laurence J Portoghese, Philip S |
| description | Both μ-opioid (MOP) and type 2 cholecystokinin (CCK2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing μ-opioid agonist and CCK2 receptor antagonist pharmacophores linked through spacers containing 16−22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK2 receptors in vivo. |
| doi_str_mv | 10.1021/jm800174p |
| format | Article |
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We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing μ-opioid agonist and CCK2 receptor antagonist pharmacophores linked through spacers containing 16−22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK2 receptors in vivo.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm800174p</identifier><identifier>PMID: 19113864</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Analgesics ; Animals ; Biological and medical sciences ; Cercopithecus aethiops ; CHO Cells ; COS Cells ; Cricetinae ; Cricetulus ; Dimerization ; Energy Transfer ; Ligands ; Magnetic Resonance Spectroscopy ; Medical sciences ; Mice ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Protein Binding ; Receptor, Cholecystokinin B - metabolism ; Receptors, Opioid, mu - metabolism</subject><ispartof>Journal of medicinal chemistry, 2009-01, Vol.52 (2), p.247-258</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a458t-69f5f041137f487a16624228c3ddb7119b1fe70f045c82fe36a994456af994ba3</citedby><cites>FETCH-LOGICAL-a458t-69f5f041137f487a16624228c3ddb7119b1fe70f045c82fe36a994456af994ba3</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/jm800174p$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm800174p$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21066255$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19113864$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Yaguo</creatorcontrib><creatorcontrib>Akgün, Eyup</creatorcontrib><creatorcontrib>Harikumar, Kaleeckal G</creatorcontrib><creatorcontrib>Hopson, Jessika</creatorcontrib><creatorcontrib>Powers, Michael D</creatorcontrib><creatorcontrib>Lunzer, Mary M</creatorcontrib><creatorcontrib>Miller, Laurence J</creatorcontrib><creatorcontrib>Portoghese, Philip S</creatorcontrib><title>Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK2) Receptors by Novel Bivalent Ligands</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Both μ-opioid (MOP) and type 2 cholecystokinin (CCK2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing μ-opioid agonist and CCK2 receptor antagonist pharmacophores linked through spacers containing 16−22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK2 receptors in vivo.</description><subject>Analgesics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cercopithecus aethiops</subject><subject>CHO Cells</subject><subject>COS Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Dimerization</subject><subject>Energy Transfer</subject><subject>Ligands</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Binding</subject><subject>Receptor, Cholecystokinin B - metabolism</subject><subject>Receptors, Opioid, mu - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkcFu1DAYhC0EotvCgRdAvoC6h4Dt2I5zQSpRgYqFRaicLcexWy9eO9jJSvtuPAPPhFFXW5A4zeH_NDP6B4BnGL3CiODXm61ACDd0fAAWmBFUUYHoQ7BAiJCKcFKfgNOcNwihGpP6MTjBLca14HQB_FUYZm0GeJFz1E5NLgYYLfz1E65HF90Azz-tvyyhCgO83o8GEtjdRm_0Pk_xuwsuwPOu-0iW8KvRZpxiyrDfw89xZzx863bKmzDBlbspBvkJeGSVz-bpQc_At3eX192HarV-f9VdrCpFmZgq3lpmES0VG0tFozDnhBIidD0MfYNx22NrGlQQpgWxpuaqbSllXNmivarPwJs733Hut2bQpUJSXo7JbVXay6ic_PcS3K28iTtJOEOCNcXg5cEgxR-zyZPcuqyN9yqYOGfJuahFy0gBl3egTjHnZOwxBCP5Zxt53Kawz_9udU8exijAiwOgslbeJhW0y0eOYFQewdg9p3SWmzinUJ75n8DfUDGiOg</recordid><startdate>20090122</startdate><enddate>20090122</enddate><creator>Zheng, Yaguo</creator><creator>Akgün, Eyup</creator><creator>Harikumar, Kaleeckal G</creator><creator>Hopson, Jessika</creator><creator>Powers, Michael D</creator><creator>Lunzer, Mary M</creator><creator>Miller, Laurence J</creator><creator>Portoghese, Philip S</creator><general>American Chemical Society</general><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>20090122</creationdate><title>Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK2) Receptors by Novel Bivalent Ligands</title><author>Zheng, Yaguo ; Akgün, Eyup ; Harikumar, Kaleeckal G ; Hopson, Jessika ; Powers, Michael D ; Lunzer, Mary M ; Miller, Laurence J ; Portoghese, Philip S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a458t-69f5f041137f487a16624228c3ddb7119b1fe70f045c82fe36a994456af994ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Analgesics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cercopithecus aethiops</topic><topic>CHO Cells</topic><topic>COS Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Dimerization</topic><topic>Energy Transfer</topic><topic>Ligands</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Binding</topic><topic>Receptor, Cholecystokinin B - metabolism</topic><topic>Receptors, Opioid, mu - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Yaguo</creatorcontrib><creatorcontrib>Akgün, Eyup</creatorcontrib><creatorcontrib>Harikumar, Kaleeckal G</creatorcontrib><creatorcontrib>Hopson, Jessika</creatorcontrib><creatorcontrib>Powers, Michael D</creatorcontrib><creatorcontrib>Lunzer, Mary M</creatorcontrib><creatorcontrib>Miller, Laurence J</creatorcontrib><creatorcontrib>Portoghese, Philip S</creatorcontrib><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>Zheng, Yaguo</au><au>Akgün, Eyup</au><au>Harikumar, Kaleeckal G</au><au>Hopson, Jessika</au><au>Powers, Michael D</au><au>Lunzer, Mary M</au><au>Miller, Laurence J</au><au>Portoghese, Philip S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK2) Receptors by Novel Bivalent Ligands</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-01-22</date><risdate>2009</risdate><volume>52</volume><issue>2</issue><spage>247</spage><epage>258</epage><pages>247-258</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Both μ-opioid (MOP) and type 2 cholecystokinin (CCK2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing μ-opioid agonist and CCK2 receptor antagonist pharmacophores linked through spacers containing 16−22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK2 receptors in vivo.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19113864</pmid><doi>10.1021/jm800174p</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2009-01, Vol.52 (2), p.247-258 |
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| subjects | Analgesics Animals Biological and medical sciences Cercopithecus aethiops CHO Cells COS Cells Cricetinae Cricetulus Dimerization Energy Transfer Ligands Magnetic Resonance Spectroscopy Medical sciences Mice Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Protein Binding Receptor, Cholecystokinin B - metabolism Receptors, Opioid, mu - metabolism |
| title | Induced Association of μ Opioid (MOP) and Type 2 Cholecystokinin (CCK2) Receptors by Novel Bivalent Ligands |
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