Cocaine receptors labeled by [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane
The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation, and competition experiments indicated that [...
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| Veröffentlicht in: | Molecular pharmacology 1989-10, Vol.36 (4), p.518-524 |
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| creator | MADRAS, B. K SPEALMAN, R. D FAHEY, M. A NEUMEYER, J. L SAHA, J. K MILIUS, R. A |
| description | The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated
and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation,
and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation
of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5
and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7
+/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT
was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine.
Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast, several monoamine uptake
inhibitors structurally unrelated to cocaine (GBR 12909, Lu 19-005, and mazindol) displaced a maximum of about 90% specifically
bound [3H]CFT, with steeper competition curves (nH, 0.89-1.3), suggesting that these drugs bind to a subpopulation of [3H]CFT-labeled
sites. The rank order of potency observed in the present study is identical to the rank order of potency at binding sites
labeled by [3H]cocaine: Lu 19-005 greater than mazindol greater than CFT greater than GBR 12909 greater than (-)-cocaine greater
than bupropion greater than WIN 35,140 greater than (+)-cocaine. Moreover, there is a high positive correlation (r, 0.99,
p less than 0.001) between the affinities of drugs at sites labeled by [3H]CFT and [3H]cocaine. The results show that [3H]CFT
and [3H]cocaine bind to a similar spectrum of sites in monkey caudate putamen. Because of its higher affinity and slower dissociation
rate, [3H]CFT appears to be a superior radioligand probe for these sites. |
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and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation,
and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation
of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5
and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7
+/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT
was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine.
Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast, several monoamine uptake
inhibitors structurally unrelated to cocaine (GBR 12909, Lu 19-005, and mazindol) displaced a maximum of about 90% specifically
bound [3H]CFT, with steeper competition curves (nH, 0.89-1.3), suggesting that these drugs bind to a subpopulation of [3H]CFT-labeled
sites. The rank order of potency observed in the present study is identical to the rank order of potency at binding sites
labeled by [3H]cocaine: Lu 19-005 greater than mazindol greater than CFT greater than GBR 12909 greater than (-)-cocaine greater
than bupropion greater than WIN 35,140 greater than (+)-cocaine. Moreover, there is a high positive correlation (r, 0.99,
p less than 0.001) between the affinities of drugs at sites labeled by [3H]CFT and [3H]cocaine. The results show that [3H]CFT
and [3H]cocaine bind to a similar spectrum of sites in monkey caudate putamen. Because of its higher affinity and slower dissociation
rate, [3H]CFT appears to be a superior radioligand probe for these sites.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 2811854</identifier><identifier>CODEN: MOPMA3</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Animals ; Binding, Competitive ; Biological and medical sciences ; Carrier Proteins ; Caudate Nucleus - metabolism ; Cocaine - analogs & derivatives ; Cocaine - metabolism ; Drug addictions ; In Vitro Techniques ; Kinetics ; Macaca fascicularis ; Medical sciences ; Putamen - metabolism ; Receptors, Drug - metabolism ; Toxicology</subject><ispartof>Molecular pharmacology, 1989-10, Vol.36 (4), p.518-524</ispartof><rights>1990 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=6708400$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2811854$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MADRAS, B. K</creatorcontrib><creatorcontrib>SPEALMAN, R. D</creatorcontrib><creatorcontrib>FAHEY, M. A</creatorcontrib><creatorcontrib>NEUMEYER, J. L</creatorcontrib><creatorcontrib>SAHA, J. K</creatorcontrib><creatorcontrib>MILIUS, R. A</creatorcontrib><title>Cocaine receptors labeled by [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated
and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation,
and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation
of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5
and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7
+/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT
was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine.
Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast, several monoamine uptake
inhibitors structurally unrelated to cocaine (GBR 12909, Lu 19-005, and mazindol) displaced a maximum of about 90% specifically
bound [3H]CFT, with steeper competition curves (nH, 0.89-1.3), suggesting that these drugs bind to a subpopulation of [3H]CFT-labeled
sites. The rank order of potency observed in the present study is identical to the rank order of potency at binding sites
labeled by [3H]cocaine: Lu 19-005 greater than mazindol greater than CFT greater than GBR 12909 greater than (-)-cocaine greater
than bupropion greater than WIN 35,140 greater than (+)-cocaine. Moreover, there is a high positive correlation (r, 0.99,
p less than 0.001) between the affinities of drugs at sites labeled by [3H]CFT and [3H]cocaine. The results show that [3H]CFT
and [3H]cocaine bind to a similar spectrum of sites in monkey caudate putamen. Because of its higher affinity and slower dissociation
rate, [3H]CFT appears to be a superior radioligand probe for these sites.</description><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Carrier Proteins</subject><subject>Caudate Nucleus - metabolism</subject><subject>Cocaine - analogs & derivatives</subject><subject>Cocaine - metabolism</subject><subject>Drug addictions</subject><subject>In Vitro Techniques</subject><subject>Kinetics</subject><subject>Macaca fascicularis</subject><subject>Medical sciences</subject><subject>Putamen - metabolism</subject><subject>Receptors, Drug - metabolism</subject><subject>Toxicology</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1989</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1Lw0AQhhdRaq3-BCEHFT0EZj-bHKWoFQoeVBBEwmYzaSKbbNxN0Px7Iy2eZpjnYWZ4D8icSkZjoJQekjkAU3GSyrdjchLCJwAVMoEZmbGE0kSKOXleOaPrFiOPBrve-RBZnaPFIsrH6J2vP1iUY69jo33uGuwr9zPGfDe7FnFpB-ddV2E72pt-6nSLp-So1Dbg2b4uyOv93ctqHW-eHh5Xt5u4Ykr2sZCgOQcGstApZxSBmRyhNKgoS00CSuWUgyhSoyZMi2WJBVOCJihpWgBfkKvd3s67rwFDnzV1MGjt9IMbQrZMOUAqxSSe78Uhb7DIOl832o_ZPoWJX-y5Dkbb0uvW1OFfU0tIBPzdu9xpVb2tvmuPWVdp32jjrNuOGVeZyCRN-C-zqnHc</recordid><startdate>19891001</startdate><enddate>19891001</enddate><creator>MADRAS, B. K</creator><creator>SPEALMAN, R. D</creator><creator>FAHEY, M. A</creator><creator>NEUMEYER, J. L</creator><creator>SAHA, J. K</creator><creator>MILIUS, R. A</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>7X8</scope></search><sort><creationdate>19891001</creationdate><title>Cocaine receptors labeled by [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane</title><author>MADRAS, B. K ; SPEALMAN, R. D ; FAHEY, M. A ; NEUMEYER, J. L ; SAHA, J. K ; MILIUS, R. A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h265t-450a330205da9321e02cbe0fce6129c8066b1304d9c63211d7fed26418e519d03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1989</creationdate><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Carrier Proteins</topic><topic>Caudate Nucleus - metabolism</topic><topic>Cocaine - analogs & derivatives</topic><topic>Cocaine - metabolism</topic><topic>Drug addictions</topic><topic>In Vitro Techniques</topic><topic>Kinetics</topic><topic>Macaca fascicularis</topic><topic>Medical sciences</topic><topic>Putamen - metabolism</topic><topic>Receptors, Drug - metabolism</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MADRAS, B. K</creatorcontrib><creatorcontrib>SPEALMAN, R. D</creatorcontrib><creatorcontrib>FAHEY, M. A</creatorcontrib><creatorcontrib>NEUMEYER, J. L</creatorcontrib><creatorcontrib>SAHA, J. K</creatorcontrib><creatorcontrib>MILIUS, R. A</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>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MADRAS, B. K</au><au>SPEALMAN, R. D</au><au>FAHEY, M. A</au><au>NEUMEYER, J. L</au><au>SAHA, J. K</au><au>MILIUS, R. A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cocaine receptors labeled by [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1989-10-01</date><risdate>1989</risdate><volume>36</volume><issue>4</issue><spage>518</spage><epage>524</epage><pages>518-524</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><coden>MOPMA3</coden><abstract>The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated
and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation,
and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation
of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5
and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7
+/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT
was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine.
Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast, several monoamine uptake
inhibitors structurally unrelated to cocaine (GBR 12909, Lu 19-005, and mazindol) displaced a maximum of about 90% specifically
bound [3H]CFT, with steeper competition curves (nH, 0.89-1.3), suggesting that these drugs bind to a subpopulation of [3H]CFT-labeled
sites. The rank order of potency observed in the present study is identical to the rank order of potency at binding sites
labeled by [3H]cocaine: Lu 19-005 greater than mazindol greater than CFT greater than GBR 12909 greater than (-)-cocaine greater
than bupropion greater than WIN 35,140 greater than (+)-cocaine. Moreover, there is a high positive correlation (r, 0.99,
p less than 0.001) between the affinities of drugs at sites labeled by [3H]CFT and [3H]cocaine. The results show that [3H]CFT
and [3H]cocaine bind to a similar spectrum of sites in monkey caudate putamen. Because of its higher affinity and slower dissociation
rate, [3H]CFT appears to be a superior radioligand probe for these sites.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>2811854</pmid><tpages>7</tpages></addata></record> |
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| ispartof | Molecular pharmacology, 1989-10, Vol.36 (4), p.518-524 |
| issn | 0026-895X 1521-0111 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_79300954 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Binding, Competitive Biological and medical sciences Carrier Proteins Caudate Nucleus - metabolism Cocaine - analogs & derivatives Cocaine - metabolism Drug addictions In Vitro Techniques Kinetics Macaca fascicularis Medical sciences Putamen - metabolism Receptors, Drug - metabolism Toxicology |
| title | Cocaine receptors labeled by [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane |
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