BW373U86: a nonpeptidic delta-opioid agonist with novel receptor-G protein-mediated actions in rat brain membranes and neuroblastoma cells
BW373U86 is a potent and highly selective nonpeptidic agonist for delta-opioid receptors. To determine its ability to couple with G protein-linked second messenger systems, this study examined the effects of BW373U86 on the inhibition of adenylyl cyclase and the stimulation of low-Km GTPase activity...
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| Veröffentlicht in: | Molecular pharmacology 1993-10, Vol.44 (4), p.827-834 |
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| creator | CHILDERS, S. R FLEMING, L. M SELLEY, D. E MCNUTT, R. W KWEN-JEN CHANG |
| description | BW373U86 is a potent and highly selective nonpeptidic agonist for delta-opioid receptors. To determine its ability to couple
with G protein-linked second messenger systems, this study examined the effects of BW373U86 on the inhibition of adenylyl
cyclase and the stimulation of low-Km GTPase activity. In rat striatal membranes, BW373U86 inhibited basal adenylyl cyclase
activity in a GTP-dependent manner, with maximal inhibition levels similar to those of the prototypic delta agonist [D-Ser2,Thr6]Leu-enkephalin
(DSLET). However, BW373U86 was approximately 100 times more potent than DSLET in inhibiting adenylyl cyclase. Analysis of
the inhibitory activity across 10 brain regions revealed that both low and high concentrations of BW373U86 inhibited adenylyl
cyclase activity in a manner similar to that of DSLET. Inhibition of adenylyl cyclase by BW373U86 was delta receptor selective,
because the delta receptor-selective antagonist naltrindole was significantly more potent than naloxone and the mu receptor-selective
antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 was ineffective in blocking BW373U86 inhibition. BW373U86 also inhibited
adenylyl cyclase activity in membranes prepared from NG108-15 cells, with an IC50 value 5 times lower than that of DSLET.
This increased potency was not observed in concentration-effect curves for agonist-stimulated low-Km GTPase in NG108-15 membranes.
BW373U86 is a competitive inhibitor of [3H]diprenorphine at delta receptors of NG108-15 cell membranes. However, unlike DSLET,
BW373U86 displacement of [3H]diprenorphine binding to NG108-15 cell membranes was not affected by sodium and guanine nucleotides.
This lack of GTP effect on binding apparently produced slow dissociation rates for this agonist, because naltrindole was less
potent in blocking BW373U86 inhibition of adenylyl cyclase when membranes were preincubated with this agonist. These results
demonstrate the novel finding that the binding of a full agonist to a G protein-coupled receptor is not regulated by GTP,
and they also show how the lack of regulation in receptor binding affects agonist potency. |
| format | Article |
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with G protein-linked second messenger systems, this study examined the effects of BW373U86 on the inhibition of adenylyl
cyclase and the stimulation of low-Km GTPase activity. In rat striatal membranes, BW373U86 inhibited basal adenylyl cyclase
activity in a GTP-dependent manner, with maximal inhibition levels similar to those of the prototypic delta agonist [D-Ser2,Thr6]Leu-enkephalin
(DSLET). However, BW373U86 was approximately 100 times more potent than DSLET in inhibiting adenylyl cyclase. Analysis of
the inhibitory activity across 10 brain regions revealed that both low and high concentrations of BW373U86 inhibited adenylyl
cyclase activity in a manner similar to that of DSLET. Inhibition of adenylyl cyclase by BW373U86 was delta receptor selective,
because the delta receptor-selective antagonist naltrindole was significantly more potent than naloxone and the mu receptor-selective
antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 was ineffective in blocking BW373U86 inhibition. BW373U86 also inhibited
adenylyl cyclase activity in membranes prepared from NG108-15 cells, with an IC50 value 5 times lower than that of DSLET.
This increased potency was not observed in concentration-effect curves for agonist-stimulated low-Km GTPase in NG108-15 membranes.
BW373U86 is a competitive inhibitor of [3H]diprenorphine at delta receptors of NG108-15 cell membranes. However, unlike DSLET,
BW373U86 displacement of [3H]diprenorphine binding to NG108-15 cell membranes was not affected by sodium and guanine nucleotides.
This lack of GTP effect on binding apparently produced slow dissociation rates for this agonist, because naltrindole was less
potent in blocking BW373U86 inhibition of adenylyl cyclase when membranes were preincubated with this agonist. These results
demonstrate the novel finding that the binding of a full agonist to a G protein-coupled receptor is not regulated by GTP,
and they also show how the lack of regulation in receptor binding affects agonist potency.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 8232233</identifier><identifier>CODEN: MOPMA3</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Adenylyl Cyclase Inhibitors ; Amino Acid Sequence ; Animals ; Benzamides - pharmacology ; Biological and medical sciences ; Brain - drug effects ; Brain - enzymology ; Brain - physiology ; Corpus Striatum - enzymology ; GTP Phosphohydrolases - drug effects ; GTP Phosphohydrolases - metabolism ; GTP-Binding Proteins - drug effects ; GTP-Binding Proteins - physiology ; Guanine Nucleotides - physiology ; Hydrogen-Ion Concentration ; Kinetics ; Male ; Medical sciences ; Membranes - drug effects ; Membranes - enzymology ; Membranes - physiology ; Molecular Sequence Data ; Neuroblastoma - drug therapy ; Neuroblastoma - physiopathology ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Piperazines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, delta - drug effects ; Receptors, Opioid, delta - physiology ; Second Messenger Systems - physiology ; Sodium - physiology ; Stimulation, Chemical ; Tumor Cells, Cultured - drug effects</subject><ispartof>Molecular pharmacology, 1993-10, Vol.44 (4), p.827-834</ispartof><rights>1994 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3786116$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8232233$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CHILDERS, S. R</creatorcontrib><creatorcontrib>FLEMING, L. M</creatorcontrib><creatorcontrib>SELLEY, D. E</creatorcontrib><creatorcontrib>MCNUTT, R. W</creatorcontrib><creatorcontrib>KWEN-JEN CHANG</creatorcontrib><title>BW373U86: a nonpeptidic delta-opioid agonist with novel receptor-G protein-mediated actions in rat brain membranes and neuroblastoma cells</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>BW373U86 is a potent and highly selective nonpeptidic agonist for delta-opioid receptors. To determine its ability to couple
with G protein-linked second messenger systems, this study examined the effects of BW373U86 on the inhibition of adenylyl
cyclase and the stimulation of low-Km GTPase activity. In rat striatal membranes, BW373U86 inhibited basal adenylyl cyclase
activity in a GTP-dependent manner, with maximal inhibition levels similar to those of the prototypic delta agonist [D-Ser2,Thr6]Leu-enkephalin
(DSLET). However, BW373U86 was approximately 100 times more potent than DSLET in inhibiting adenylyl cyclase. Analysis of
the inhibitory activity across 10 brain regions revealed that both low and high concentrations of BW373U86 inhibited adenylyl
cyclase activity in a manner similar to that of DSLET. Inhibition of adenylyl cyclase by BW373U86 was delta receptor selective,
because the delta receptor-selective antagonist naltrindole was significantly more potent than naloxone and the mu receptor-selective
antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 was ineffective in blocking BW373U86 inhibition. BW373U86 also inhibited
adenylyl cyclase activity in membranes prepared from NG108-15 cells, with an IC50 value 5 times lower than that of DSLET.
This increased potency was not observed in concentration-effect curves for agonist-stimulated low-Km GTPase in NG108-15 membranes.
BW373U86 is a competitive inhibitor of [3H]diprenorphine at delta receptors of NG108-15 cell membranes. However, unlike DSLET,
BW373U86 displacement of [3H]diprenorphine binding to NG108-15 cell membranes was not affected by sodium and guanine nucleotides.
This lack of GTP effect on binding apparently produced slow dissociation rates for this agonist, because naltrindole was less
potent in blocking BW373U86 inhibition of adenylyl cyclase when membranes were preincubated with this agonist. These results
demonstrate the novel finding that the binding of a full agonist to a G protein-coupled receptor is not regulated by GTP,
and they also show how the lack of regulation in receptor binding affects agonist potency.</description><subject>Adenylyl Cyclase Inhibitors</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Benzamides - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Brain - drug effects</subject><subject>Brain - enzymology</subject><subject>Brain - physiology</subject><subject>Corpus Striatum - enzymology</subject><subject>GTP Phosphohydrolases - drug effects</subject><subject>GTP Phosphohydrolases - metabolism</subject><subject>GTP-Binding Proteins - drug effects</subject><subject>GTP-Binding Proteins - physiology</subject><subject>Guanine Nucleotides - physiology</subject><subject>Hydrogen-Ion Concentration</subject><subject>Kinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membranes - drug effects</subject><subject>Membranes - enzymology</subject><subject>Membranes - physiology</subject><subject>Molecular Sequence Data</subject><subject>Neuroblastoma - drug therapy</subject><subject>Neuroblastoma - physiopathology</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>Piperazines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Opioid, delta - drug effects</subject><subject>Receptors, Opioid, delta - physiology</subject><subject>Second Messenger Systems - physiology</subject><subject>Sodium - physiology</subject><subject>Stimulation, Chemical</subject><subject>Tumor Cells, Cultured - drug effects</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM9KHTEYxQdpsVfbRxCyaLsbyJ-ZTOKuirWC4Eapu-Gb5Js7KTPJmOQqvoJP3YgXt67OgfPjcDgH1Ya1nNWUMfap2lDKZa10e_-lOkrpH6WsaRU9rA4VF5wLsalezv6KTtwpeUqA-OBXXLOzzhCLc4Y6rC44S2AbvEuZPLk8FeoRZxLRFDTE-pKsMWR0vl7QOshYcJNd8Ik4TyJkMkQobsGlGI-JgLfE4y6GYYaUwwLE4Dynr9XnEeaE3_Z6XN39vrg9_1Nf31xenf-6rieuZa6tHYwUqsEGAQatKBdKWythYF3LYGSSGia0koI1Ro0MgXaKc0VRjQa1EcfVz7fesvthhyn3i0uvC8q4sEt9J2mrNdcfgkyqVlMhC3iyB3dDOaFfo1sgPvf7l0v-fZ9DMjCP5Qbj0jsmOiUZe6358YZNbjs9uYj9OkFcwIQ5bJ_7pumbUtmJ_4o-lPs</recordid><startdate>19931001</startdate><enddate>19931001</enddate><creator>CHILDERS, S. R</creator><creator>FLEMING, L. M</creator><creator>SELLEY, D. E</creator><creator>MCNUTT, R. W</creator><creator>KWEN-JEN CHANG</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>19931001</creationdate><title>BW373U86: a nonpeptidic delta-opioid agonist with novel receptor-G protein-mediated actions in rat brain membranes and neuroblastoma cells</title><author>CHILDERS, S. R ; FLEMING, L. M ; SELLEY, D. E ; MCNUTT, R. W ; KWEN-JEN CHANG</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h296t-ddbc6384e4eaab9802389dd6ab1751af160c13986314c8f1ea0782280e8fce9c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Adenylyl Cyclase Inhibitors</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Benzamides - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Brain - drug effects</topic><topic>Brain - enzymology</topic><topic>Brain - physiology</topic><topic>Corpus Striatum - enzymology</topic><topic>GTP Phosphohydrolases - drug effects</topic><topic>GTP Phosphohydrolases - metabolism</topic><topic>GTP-Binding Proteins - drug effects</topic><topic>GTP-Binding Proteins - physiology</topic><topic>Guanine Nucleotides - physiology</topic><topic>Hydrogen-Ion Concentration</topic><topic>Kinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membranes - drug effects</topic><topic>Membranes - enzymology</topic><topic>Membranes - physiology</topic><topic>Molecular Sequence Data</topic><topic>Neuroblastoma - drug therapy</topic><topic>Neuroblastoma - physiopathology</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>Piperazines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Opioid, delta - drug effects</topic><topic>Receptors, Opioid, delta - physiology</topic><topic>Second Messenger Systems - physiology</topic><topic>Sodium - physiology</topic><topic>Stimulation, Chemical</topic><topic>Tumor Cells, Cultured - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHILDERS, S. R</creatorcontrib><creatorcontrib>FLEMING, L. M</creatorcontrib><creatorcontrib>SELLEY, D. E</creatorcontrib><creatorcontrib>MCNUTT, R. W</creatorcontrib><creatorcontrib>KWEN-JEN CHANG</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>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHILDERS, S. R</au><au>FLEMING, L. M</au><au>SELLEY, D. E</au><au>MCNUTT, R. W</au><au>KWEN-JEN CHANG</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BW373U86: a nonpeptidic delta-opioid agonist with novel receptor-G protein-mediated actions in rat brain membranes and neuroblastoma cells</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1993-10-01</date><risdate>1993</risdate><volume>44</volume><issue>4</issue><spage>827</spage><epage>834</epage><pages>827-834</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><coden>MOPMA3</coden><abstract>BW373U86 is a potent and highly selective nonpeptidic agonist for delta-opioid receptors. To determine its ability to couple
with G protein-linked second messenger systems, this study examined the effects of BW373U86 on the inhibition of adenylyl
cyclase and the stimulation of low-Km GTPase activity. In rat striatal membranes, BW373U86 inhibited basal adenylyl cyclase
activity in a GTP-dependent manner, with maximal inhibition levels similar to those of the prototypic delta agonist [D-Ser2,Thr6]Leu-enkephalin
(DSLET). However, BW373U86 was approximately 100 times more potent than DSLET in inhibiting adenylyl cyclase. Analysis of
the inhibitory activity across 10 brain regions revealed that both low and high concentrations of BW373U86 inhibited adenylyl
cyclase activity in a manner similar to that of DSLET. Inhibition of adenylyl cyclase by BW373U86 was delta receptor selective,
because the delta receptor-selective antagonist naltrindole was significantly more potent than naloxone and the mu receptor-selective
antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 was ineffective in blocking BW373U86 inhibition. BW373U86 also inhibited
adenylyl cyclase activity in membranes prepared from NG108-15 cells, with an IC50 value 5 times lower than that of DSLET.
This increased potency was not observed in concentration-effect curves for agonist-stimulated low-Km GTPase in NG108-15 membranes.
BW373U86 is a competitive inhibitor of [3H]diprenorphine at delta receptors of NG108-15 cell membranes. However, unlike DSLET,
BW373U86 displacement of [3H]diprenorphine binding to NG108-15 cell membranes was not affected by sodium and guanine nucleotides.
This lack of GTP effect on binding apparently produced slow dissociation rates for this agonist, because naltrindole was less
potent in blocking BW373U86 inhibition of adenylyl cyclase when membranes were preincubated with this agonist. These results
demonstrate the novel finding that the binding of a full agonist to a G protein-coupled receptor is not regulated by GTP,
and they also show how the lack of regulation in receptor binding affects agonist potency.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>8232233</pmid><tpages>8</tpages></addata></record> |
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| ispartof | Molecular pharmacology, 1993-10, Vol.44 (4), p.827-834 |
| issn | 0026-895X 1521-0111 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_76059929 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Adenylyl Cyclase Inhibitors Amino Acid Sequence Animals Benzamides - pharmacology Biological and medical sciences Brain - drug effects Brain - enzymology Brain - physiology Corpus Striatum - enzymology GTP Phosphohydrolases - drug effects GTP Phosphohydrolases - metabolism GTP-Binding Proteins - drug effects GTP-Binding Proteins - physiology Guanine Nucleotides - physiology Hydrogen-Ion Concentration Kinetics Male Medical sciences Membranes - drug effects Membranes - enzymology Membranes - physiology Molecular Sequence Data Neuroblastoma - drug therapy Neuroblastoma - physiopathology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Piperazines - pharmacology Rats Rats, Sprague-Dawley Receptors, Opioid, delta - drug effects Receptors, Opioid, delta - physiology Second Messenger Systems - physiology Sodium - physiology Stimulation, Chemical Tumor Cells, Cultured - drug effects |
| title | BW373U86: a nonpeptidic delta-opioid agonist with novel receptor-G protein-mediated actions in rat brain membranes and neuroblastoma cells |
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