Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives
A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (K i = 11−22 nM) to the dopamine transporter...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 1997-03, Vol.40 (6), p.858-863 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 863 |
|---|---|
| container_issue | 6 |
| container_start_page | 858 |
| container_title | Journal of medicinal chemistry |
| container_volume | 40 |
| creator | Xu, Lifen Kelkar, Shreekrishna V Lomenzo, Stacey A Izenwasser, Sari Katz, Jonathan L Kline, Richard H Trudell, Mark L |
| description | A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (K i = 11−22 nM) to the dopamine transporter. Increased lipophilicity at the β-C(2)-position was found to lead to increased binding affinity and increased dopamine uptake potency. However, a direct correlation between clogP values and binding affinity and potency of uptake inhibition was not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition relative to the high binding affinity (IC50/K i = 10.2). In vivo measurement of stimulated locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs (4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately equipotent with those of cocaine. The structure−activity relationships of this series of cocaine analogs supports a pharmacophore model in which lipophilic interactions between the β-C(2)-position of 3β-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect. |
| doi_str_mv | 10.1021/jm960739c |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_78918919</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>78918919</sourcerecordid><originalsourceid>FETCH-LOGICAL-a377t-9a244a56e122e12e3c8e4e393eaed5a436523f0c005f4330baeeb33c330f9b6b3</originalsourceid><addsrcrecordid>eNptkd9qFDEUxoNY6lq98AGEXKggdDT_Zmbncm3tH1yxsFsvvAmZ7Amb7UwyJpniPkhfpA_iMxnZZfFCyCEHvt_5OHwHoVeUfKCE0Y-bvqlIzRv9BE1oyUghpkQ8RRNCGCtYxfgz9DzGDSGEU8aP0XFDplzUYoIeFluX1hBtPMXnflC9dYCXQbk4-JAg4Jkx1tm0_Ue-HZK6A3zt1ra1yXp3ipVb4bnXvvfJB7xIth875RKe6WTv8zT2BrNiMbYx2TQmWGH--7G4WYPbdilk42x7DsHeq8xDfIGOjOoivNz_J-j24vPy7KqYf7u8PpvNC8XrOhWNYkKosgLKWC7gegoCeMNBwapUglcl44ZoQkojOCetAmg517k1TVu1_AS92_kOwf8cISbZ26ihy7uDH6Ospw3Nr8ng-x2og48xgJFDsL0KW0mJ_HsCeThBZl_vTce2h9WB3Gee9Td7XUWtOpPD1jYeMFYRWpU0Y8UOszHBr4Oswp2sal6XcnmzkFdfv1yQH98_yTLzb3e80lFu_BhcTu4_6_0Br4CslA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>78918919</pqid></control><display><type>article</type><title>Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives</title><source>MEDLINE</source><source>American Chemical Society Web Editions</source><creator>Xu, Lifen ; Kelkar, Shreekrishna V ; Lomenzo, Stacey A ; Izenwasser, Sari ; Katz, Jonathan L ; Kline, Richard H ; Trudell, Mark L</creator><creatorcontrib>Xu, Lifen ; Kelkar, Shreekrishna V ; Lomenzo, Stacey A ; Izenwasser, Sari ; Katz, Jonathan L ; Kline, Richard H ; Trudell, Mark L</creatorcontrib><description>A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (K i = 11−22 nM) to the dopamine transporter. Increased lipophilicity at the β-C(2)-position was found to lead to increased binding affinity and increased dopamine uptake potency. However, a direct correlation between clogP values and binding affinity and potency of uptake inhibition was not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition relative to the high binding affinity (IC50/K i = 10.2). In vivo measurement of stimulated locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs (4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately equipotent with those of cocaine. The structure−activity relationships of this series of cocaine analogs supports a pharmacophore model in which lipophilic interactions between the β-C(2)-position of 3β-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm960739c</identifier><identifier>PMID: 9083474</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Binding Sites ; Binding, Competitive ; Biological and medical sciences ; Brain - drug effects ; Carrier Proteins - antagonists & inhibitors ; Carrier Proteins - metabolism ; Catecholaminergic system ; Cocaine - analogs & derivatives ; Cocaine - metabolism ; Cocaine - pharmacology ; Dopamine - metabolism ; Dopamine Plasma Membrane Transport Proteins ; Dopamine Uptake Inhibitors - chemical synthesis ; Dopamine Uptake Inhibitors - chemistry ; Dopamine Uptake Inhibitors - metabolism ; Dopamine Uptake Inhibitors - pharmacology ; Dose-Response Relationship, Drug ; Magnetic Resonance Spectroscopy ; Medical sciences ; Membrane Glycoproteins ; Membrane Transport Proteins ; Molecular Structure ; Motor Activity - drug effects ; Nerve Tissue Proteins ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Rats ; Tropanes - chemical synthesis ; Tropanes - chemistry ; Tropanes - metabolism ; Tropanes - pharmacology</subject><ispartof>Journal of medicinal chemistry, 1997-03, Vol.40 (6), p.858-863</ispartof><rights>Copyright © 1997 American Chemical Society</rights><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a377t-9a244a56e122e12e3c8e4e393eaed5a436523f0c005f4330baeeb33c330f9b6b3</citedby><cites>FETCH-LOGICAL-a377t-9a244a56e122e12e3c8e4e393eaed5a436523f0c005f4330baeeb33c330f9b6b3</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/jm960739c$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm960739c$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2601651$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9083474$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Lifen</creatorcontrib><creatorcontrib>Kelkar, Shreekrishna V</creatorcontrib><creatorcontrib>Lomenzo, Stacey A</creatorcontrib><creatorcontrib>Izenwasser, Sari</creatorcontrib><creatorcontrib>Katz, Jonathan L</creatorcontrib><creatorcontrib>Kline, Richard H</creatorcontrib><creatorcontrib>Trudell, Mark L</creatorcontrib><title>Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (K i = 11−22 nM) to the dopamine transporter. Increased lipophilicity at the β-C(2)-position was found to lead to increased binding affinity and increased dopamine uptake potency. However, a direct correlation between clogP values and binding affinity and potency of uptake inhibition was not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition relative to the high binding affinity (IC50/K i = 10.2). In vivo measurement of stimulated locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs (4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately equipotent with those of cocaine. The structure−activity relationships of this series of cocaine analogs supports a pharmacophore model in which lipophilic interactions between the β-C(2)-position of 3β-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Brain - drug effects</subject><subject>Carrier Proteins - antagonists & inhibitors</subject><subject>Carrier Proteins - metabolism</subject><subject>Catecholaminergic system</subject><subject>Cocaine - analogs & derivatives</subject><subject>Cocaine - metabolism</subject><subject>Cocaine - pharmacology</subject><subject>Dopamine - metabolism</subject><subject>Dopamine Plasma Membrane Transport Proteins</subject><subject>Dopamine Uptake Inhibitors - chemical synthesis</subject><subject>Dopamine Uptake Inhibitors - chemistry</subject><subject>Dopamine Uptake Inhibitors - metabolism</subject><subject>Dopamine Uptake Inhibitors - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Membrane Glycoproteins</subject><subject>Membrane Transport Proteins</subject><subject>Molecular Structure</subject><subject>Motor Activity - drug effects</subject><subject>Nerve Tissue Proteins</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Tropanes - chemical synthesis</subject><subject>Tropanes - chemistry</subject><subject>Tropanes - metabolism</subject><subject>Tropanes - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkd9qFDEUxoNY6lq98AGEXKggdDT_Zmbncm3tH1yxsFsvvAmZ7Amb7UwyJpniPkhfpA_iMxnZZfFCyCEHvt_5OHwHoVeUfKCE0Y-bvqlIzRv9BE1oyUghpkQ8RRNCGCtYxfgz9DzGDSGEU8aP0XFDplzUYoIeFluX1hBtPMXnflC9dYCXQbk4-JAg4Jkx1tm0_Ue-HZK6A3zt1ra1yXp3ipVb4bnXvvfJB7xIth875RKe6WTv8zT2BrNiMbYx2TQmWGH--7G4WYPbdilk42x7DsHeq8xDfIGOjOoivNz_J-j24vPy7KqYf7u8PpvNC8XrOhWNYkKosgLKWC7gegoCeMNBwapUglcl44ZoQkojOCetAmg517k1TVu1_AS92_kOwf8cISbZ26ihy7uDH6Ospw3Nr8ng-x2og48xgJFDsL0KW0mJ_HsCeThBZl_vTce2h9WB3Gee9Td7XUWtOpPD1jYeMFYRWpU0Y8UOszHBr4Oswp2sal6XcnmzkFdfv1yQH98_yTLzb3e80lFu_BhcTu4_6_0Br4CslA</recordid><startdate>19970314</startdate><enddate>19970314</enddate><creator>Xu, Lifen</creator><creator>Kelkar, Shreekrishna V</creator><creator>Lomenzo, Stacey A</creator><creator>Izenwasser, Sari</creator><creator>Katz, Jonathan L</creator><creator>Kline, Richard H</creator><creator>Trudell, Mark L</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>7X8</scope></search><sort><creationdate>19970314</creationdate><title>Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives</title><author>Xu, Lifen ; Kelkar, Shreekrishna V ; Lomenzo, Stacey A ; Izenwasser, Sari ; Katz, Jonathan L ; Kline, Richard H ; Trudell, Mark L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a377t-9a244a56e122e12e3c8e4e393eaed5a436523f0c005f4330baeeb33c330f9b6b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Brain - drug effects</topic><topic>Carrier Proteins - antagonists & inhibitors</topic><topic>Carrier Proteins - metabolism</topic><topic>Catecholaminergic system</topic><topic>Cocaine - analogs & derivatives</topic><topic>Cocaine - metabolism</topic><topic>Cocaine - pharmacology</topic><topic>Dopamine - metabolism</topic><topic>Dopamine Plasma Membrane Transport Proteins</topic><topic>Dopamine Uptake Inhibitors - chemical synthesis</topic><topic>Dopamine Uptake Inhibitors - chemistry</topic><topic>Dopamine Uptake Inhibitors - metabolism</topic><topic>Dopamine Uptake Inhibitors - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Medical sciences</topic><topic>Membrane Glycoproteins</topic><topic>Membrane Transport Proteins</topic><topic>Molecular Structure</topic><topic>Motor Activity - drug effects</topic><topic>Nerve Tissue Proteins</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Tropanes - chemical synthesis</topic><topic>Tropanes - chemistry</topic><topic>Tropanes - metabolism</topic><topic>Tropanes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Lifen</creatorcontrib><creatorcontrib>Kelkar, Shreekrishna V</creatorcontrib><creatorcontrib>Lomenzo, Stacey A</creatorcontrib><creatorcontrib>Izenwasser, Sari</creatorcontrib><creatorcontrib>Katz, Jonathan L</creatorcontrib><creatorcontrib>Kline, Richard H</creatorcontrib><creatorcontrib>Trudell, Mark L</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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Lifen</au><au>Kelkar, Shreekrishna V</au><au>Lomenzo, Stacey A</au><au>Izenwasser, Sari</au><au>Katz, Jonathan L</au><au>Kline, Richard H</au><au>Trudell, Mark L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1997-03-14</date><risdate>1997</risdate><volume>40</volume><issue>6</issue><spage>858</spage><epage>863</epage><pages>858-863</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (K i = 11−22 nM) to the dopamine transporter. Increased lipophilicity at the β-C(2)-position was found to lead to increased binding affinity and increased dopamine uptake potency. However, a direct correlation between clogP values and binding affinity and potency of uptake inhibition was not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition relative to the high binding affinity (IC50/K i = 10.2). In vivo measurement of stimulated locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs (4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately equipotent with those of cocaine. The structure−activity relationships of this series of cocaine analogs supports a pharmacophore model in which lipophilic interactions between the β-C(2)-position of 3β-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9083474</pmid><doi>10.1021/jm960739c</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1997-03, Vol.40 (6), p.858-863 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_78918919 |
| source | MEDLINE; American Chemical Society Web Editions |
| subjects | Animals Binding Sites Binding, Competitive Biological and medical sciences Brain - drug effects Carrier Proteins - antagonists & inhibitors Carrier Proteins - metabolism Catecholaminergic system Cocaine - analogs & derivatives Cocaine - metabolism Cocaine - pharmacology Dopamine - metabolism Dopamine Plasma Membrane Transport Proteins Dopamine Uptake Inhibitors - chemical synthesis Dopamine Uptake Inhibitors - chemistry Dopamine Uptake Inhibitors - metabolism Dopamine Uptake Inhibitors - pharmacology Dose-Response Relationship, Drug Magnetic Resonance Spectroscopy Medical sciences Membrane Glycoproteins Membrane Transport Proteins Molecular Structure Motor Activity - drug effects Nerve Tissue Proteins Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Rats Tropanes - chemical synthesis Tropanes - chemistry Tropanes - metabolism Tropanes - pharmacology |
| title | Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T17%3A01%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synthesis,%20Dopamine%20Transporter%20Affinity,%20Dopamine%20Uptake%20Inhibition,%20and%20Locomotor%20Stimulant%20Activity%20of%202-Substituted%203%CE%B2-Phenyltropane%20Derivatives&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Xu,%20Lifen&rft.date=1997-03-14&rft.volume=40&rft.issue=6&rft.spage=858&rft.epage=863&rft.pages=858-863&rft.issn=0022-2623&rft.eissn=1520-4804&rft.coden=JMCMAR&rft_id=info:doi/10.1021/jm960739c&rft_dat=%3Cproquest_cross%3E78918919%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=78918919&rft_id=info:pmid/9083474&rfr_iscdi=true |