High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice
The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instabilit...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-08, Vol.58 (15), p.6195-6213 |
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| container_title | Journal of medicinal chemistry |
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| creator | Boateng, Comfort A Bakare, Oluyomi M Zhan, Jia Banala, Ashwini K Burzynski, Caitlin Pommier, Elie Keck, Thomas M Donthamsetti, Prashant Javitch, Jonathan A Rais, Rana Slusher, Barbara S Xi, Zheng-Xiong Newman, Amy Hauck |
| description | The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (Ki = 0.12 nM) and 32 (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice. |
| doi_str_mv | 10.1021/acs.jmedchem.5b00776 |
| format | Article |
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Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (Ki = 0.12 nM) and 32 (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.5b00776</identifier><identifier>PMID: 26203768</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Dopamine Antagonists - chemistry ; Dopamine Antagonists - pharmacology ; Heroin - administration & dosage ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Radioligand Assay ; Receptors, Dopamine D3 - antagonists & inhibitors ; Receptors, Dopamine D3 - genetics ; Self Administration</subject><ispartof>Journal of medicinal chemistry, 2015-08, Vol.58 (15), p.6195-6213</ispartof><rights>Copyright © 2015 American Chemical Society</rights><rights>Copyright © 2015 American Chemical Society 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b00776$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00776$$EHTML$$P50$$Gacs$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26203768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Boateng, Comfort A</creatorcontrib><creatorcontrib>Bakare, Oluyomi M</creatorcontrib><creatorcontrib>Zhan, Jia</creatorcontrib><creatorcontrib>Banala, Ashwini K</creatorcontrib><creatorcontrib>Burzynski, Caitlin</creatorcontrib><creatorcontrib>Pommier, Elie</creatorcontrib><creatorcontrib>Keck, Thomas M</creatorcontrib><creatorcontrib>Donthamsetti, Prashant</creatorcontrib><creatorcontrib>Javitch, Jonathan A</creatorcontrib><creatorcontrib>Rais, Rana</creatorcontrib><creatorcontrib>Slusher, Barbara S</creatorcontrib><creatorcontrib>Xi, Zheng-Xiong</creatorcontrib><creatorcontrib>Newman, Amy Hauck</creatorcontrib><title>High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (Ki = 0.12 nM) and 32 (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice.</description><subject>Animals</subject><subject>Dopamine Antagonists - chemistry</subject><subject>Dopamine Antagonists - pharmacology</subject><subject>Heroin - administration & dosage</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Radioligand Assay</subject><subject>Receptors, Dopamine D3 - antagonists & inhibitors</subject><subject>Receptors, Dopamine D3 - genetics</subject><subject>Self Administration</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>EIF</sourceid><recordid>eNpVUcFOGzEQtSqqJtD-QYV8hMOmY3vXXi5IKwIElapSStWj5fXOJg6Jvdp1kPILfHUNSRE9jfTmzZt58wj5ymDCgLNvxg6T1QYbu8TNpKgBlJIfyJgVHLK8hPyIjAE4z7jkYkSOh2EFAIJx8YmMEgZCyXJMnmdusaRV2zrv4o5OQ2c2ziOdCjpHi10MPT2bivl59gvXaKN7Qlr5aBbBuyEOtIoR_dZEpDPsg_M00dqsapJI6vcmuuBpgv-4dZM97Dqk9TZSH2LaMKfffbCPIQE_nMXP5GNr1gN-OdQT8vvm-uFqlt3_vL27qu4zw2UpM6EUNAwKyU1pJLMMLG9UiTnDOkfGZFvmRZOctwrr0nCsE_9CgrGsECpHcUIu97rdtn75H_p051p3vduYfqeDcfr_jndLvQhPOr8QqhQqCZy-F3ib_PfVRIA9IWWkV2Hb--RHM9AvwelX8BCcPgQn_gL_243z</recordid><startdate>20150813</startdate><enddate>20150813</enddate><creator>Boateng, Comfort A</creator><creator>Bakare, Oluyomi M</creator><creator>Zhan, Jia</creator><creator>Banala, Ashwini K</creator><creator>Burzynski, Caitlin</creator><creator>Pommier, Elie</creator><creator>Keck, Thomas M</creator><creator>Donthamsetti, Prashant</creator><creator>Javitch, Jonathan A</creator><creator>Rais, Rana</creator><creator>Slusher, Barbara S</creator><creator>Xi, Zheng-Xiong</creator><creator>Newman, Amy Hauck</creator><general>American Chemical Society</general><scope>N~.</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>5PM</scope></search><sort><creationdate>20150813</creationdate><title>High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice</title><author>Boateng, Comfort A ; Bakare, Oluyomi M ; Zhan, Jia ; Banala, Ashwini K ; Burzynski, Caitlin ; Pommier, Elie ; Keck, Thomas M ; Donthamsetti, Prashant ; Javitch, Jonathan A ; Rais, Rana ; Slusher, Barbara S ; Xi, Zheng-Xiong ; Newman, Amy Hauck</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a2686-3770d10562a8a61c10c2d78e41eb4e116f845d022f7eb8a2eb70d960ac15374e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Dopamine Antagonists - chemistry</topic><topic>Dopamine Antagonists - pharmacology</topic><topic>Heroin - administration & dosage</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Radioligand Assay</topic><topic>Receptors, Dopamine D3 - antagonists & inhibitors</topic><topic>Receptors, Dopamine D3 - genetics</topic><topic>Self Administration</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boateng, Comfort A</creatorcontrib><creatorcontrib>Bakare, Oluyomi M</creatorcontrib><creatorcontrib>Zhan, Jia</creatorcontrib><creatorcontrib>Banala, Ashwini K</creatorcontrib><creatorcontrib>Burzynski, Caitlin</creatorcontrib><creatorcontrib>Pommier, Elie</creatorcontrib><creatorcontrib>Keck, Thomas M</creatorcontrib><creatorcontrib>Donthamsetti, Prashant</creatorcontrib><creatorcontrib>Javitch, Jonathan A</creatorcontrib><creatorcontrib>Rais, Rana</creatorcontrib><creatorcontrib>Slusher, Barbara S</creatorcontrib><creatorcontrib>Xi, Zheng-Xiong</creatorcontrib><creatorcontrib>Newman, Amy Hauck</creatorcontrib><collection>American Chemical Society (ACS) Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</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>Boateng, Comfort A</au><au>Bakare, Oluyomi M</au><au>Zhan, Jia</au><au>Banala, Ashwini K</au><au>Burzynski, Caitlin</au><au>Pommier, Elie</au><au>Keck, Thomas M</au><au>Donthamsetti, Prashant</au><au>Javitch, Jonathan A</au><au>Rais, Rana</au><au>Slusher, Barbara S</au><au>Xi, Zheng-Xiong</au><au>Newman, Amy Hauck</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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Several high affinity D3R antagonists, including compounds 16 (Ki = 0.12 nM) and 32 (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26203768</pmid><doi>10.1021/acs.jmedchem.5b00776</doi><tpages>19</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2015-08, Vol.58 (15), p.6195-6213 |
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| subjects | Animals Dopamine Antagonists - chemistry Dopamine Antagonists - pharmacology Heroin - administration & dosage Male Mice Mice, Inbred C57BL Mice, Knockout Radioligand Assay Receptors, Dopamine D3 - antagonists & inhibitors Receptors, Dopamine D3 - genetics Self Administration |
| title | High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice |
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