Aryl 1-But-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as Potential Antipsychotic Agents: Synthesis and Structure−Activity Relationships
A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure−activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor...
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| Veröffentlicht in: | Journal of medicinal chemistry 1996-08, Vol.39 (16), p.3179-3187 |
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| container_issue | 16 |
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| container_title | Journal of medicinal chemistry |
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| creator | Glase, Shelly A Akunne, Hyacinth C Heffner, Thomas G Jaen, Juan C MacKenzie, Robert G Meltzer, Leonard T Pugsley, Thomas A Smith, Sarah J Wise, Lawrence D |
| description | A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure−activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys. |
| doi_str_mv | 10.1021/jm950721m |
| format | Article |
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The structure−activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm950721m</identifier><identifier>PMID: 8759640</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Alkynes - chemical synthesis ; Alkynes - pharmacology ; Animals ; Antipsychotic Agents - chemical synthesis ; Antipsychotic Agents - chemistry ; Antipsychotic Agents - metabolism ; Antipsychotic Agents - pharmacology ; Binding, Competitive ; Biological and medical sciences ; Brain - drug effects ; Catecholaminergic system ; Dopamine - metabolism ; Dopamine Agents - chemical synthesis ; Dopamine Agents - chemistry ; Dopamine Agents - metabolism ; Dopamine Agents - pharmacology ; Humans ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Medical sciences ; Mice ; Motor Activity - drug effects ; Neurons - drug effects ; Neurons - metabolism ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - metabolism ; Pyridines - pharmacology ; Rats ; Receptors, Dopamine D2 - metabolism ; Rodentia ; Saimiri ; Spiperone - metabolism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1996-08, Vol.39 (16), p.3179-3187</ispartof><rights>Copyright © 1996 American Chemical Society</rights><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a408t-d0b70a10f0017679e014ab36e56814085594711c0db37ce749ed28871adf752d3</citedby><cites>FETCH-LOGICAL-a408t-d0b70a10f0017679e014ab36e56814085594711c0db37ce749ed28871adf752d3</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/jm950721m$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm950721m$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3168429$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8759640$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Glase, Shelly A</creatorcontrib><creatorcontrib>Akunne, Hyacinth C</creatorcontrib><creatorcontrib>Heffner, Thomas G</creatorcontrib><creatorcontrib>Jaen, Juan C</creatorcontrib><creatorcontrib>MacKenzie, Robert G</creatorcontrib><creatorcontrib>Meltzer, Leonard T</creatorcontrib><creatorcontrib>Pugsley, Thomas A</creatorcontrib><creatorcontrib>Smith, Sarah J</creatorcontrib><creatorcontrib>Wise, Lawrence D</creatorcontrib><title>Aryl 1-But-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as Potential Antipsychotic Agents: Synthesis and Structure−Activity Relationships</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure−activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.</description><subject>Alkynes - chemical synthesis</subject><subject>Alkynes - pharmacology</subject><subject>Animals</subject><subject>Antipsychotic Agents - chemical synthesis</subject><subject>Antipsychotic Agents - chemistry</subject><subject>Antipsychotic Agents - metabolism</subject><subject>Antipsychotic Agents - pharmacology</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Brain - drug effects</subject><subject>Catecholaminergic system</subject><subject>Dopamine - metabolism</subject><subject>Dopamine Agents - chemical synthesis</subject><subject>Dopamine Agents - chemistry</subject><subject>Dopamine Agents - metabolism</subject><subject>Dopamine Agents - pharmacology</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Motor Activity - drug effects</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - metabolism</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Receptors, Dopamine D2 - metabolism</subject><subject>Rodentia</subject><subject>Saimiri</subject><subject>Spiperone - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0buO1DAUBmALgZZhoeABkFIAEtIYji-Jk-3CiOWilRh2lobG8jgO8ZAbtoNIRwkFDY-4T4JXM5oKiepY_j8dWf4RekjgOQFKXuy6IgVBSXcLLUhKAfMc-G20AKAU04yyu-ie9zsAYISyE3SSi7TIOCzQ79LNbULwyylghud-bjHHY2NuDmRJl2yZ4WCCU81cuWGcna1sb3yifLIegumDVW1SxjH6WTdDsDopP8drf3b941eymfvQGG-j76tkE9ykw-TM9c8_pQ72mw1zcmlaFezQ-yauuI_u1Kr15sFhnqKP56-uVm_wxfvXb1flBVYc8oAr2ApQBGoAIjJRGCBcbVlm0iwnUaRpwQUhGqotE9oIXpiK5rkgqqpFSit2ip7u945u-DoZH2RnvTZtq3ozTF6KnEJaAP8vJFHlWUojfLaH2g3eO1PL0dlOuVkSkDcdyWNH0T46LJ22namO8lBKzB8fcuW1amunem39kTGS5ZwWkeE9sz6Y78dYuS8yE0yk8mq9ke8-0Etyvl7JT9E_2XulvdwNk-vjF__jeX8BXIq15w</recordid><startdate>19960802</startdate><enddate>19960802</enddate><creator>Glase, Shelly A</creator><creator>Akunne, Hyacinth C</creator><creator>Heffner, Thomas G</creator><creator>Jaen, Juan C</creator><creator>MacKenzie, Robert G</creator><creator>Meltzer, Leonard T</creator><creator>Pugsley, Thomas A</creator><creator>Smith, Sarah J</creator><creator>Wise, Lawrence D</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>7QG</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>19960802</creationdate><title>Aryl 1-But-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as Potential Antipsychotic Agents: Synthesis and Structure−Activity Relationships</title><author>Glase, Shelly A ; Akunne, Hyacinth C ; Heffner, Thomas G ; Jaen, Juan C ; MacKenzie, Robert G ; Meltzer, Leonard T ; Pugsley, Thomas A ; Smith, Sarah J ; Wise, Lawrence D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a408t-d0b70a10f0017679e014ab36e56814085594711c0db37ce749ed28871adf752d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Alkynes - chemical synthesis</topic><topic>Alkynes - pharmacology</topic><topic>Animals</topic><topic>Antipsychotic Agents - chemical synthesis</topic><topic>Antipsychotic Agents - chemistry</topic><topic>Antipsychotic Agents - metabolism</topic><topic>Antipsychotic Agents - pharmacology</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Brain - drug effects</topic><topic>Catecholaminergic system</topic><topic>Dopamine - metabolism</topic><topic>Dopamine Agents - chemical synthesis</topic><topic>Dopamine Agents - chemistry</topic><topic>Dopamine Agents - metabolism</topic><topic>Dopamine Agents - pharmacology</topic><topic>Humans</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Motor Activity - drug effects</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - metabolism</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Receptors, Dopamine D2 - metabolism</topic><topic>Rodentia</topic><topic>Saimiri</topic><topic>Spiperone - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Glase, Shelly A</creatorcontrib><creatorcontrib>Akunne, Hyacinth C</creatorcontrib><creatorcontrib>Heffner, Thomas G</creatorcontrib><creatorcontrib>Jaen, Juan C</creatorcontrib><creatorcontrib>MacKenzie, Robert G</creatorcontrib><creatorcontrib>Meltzer, Leonard T</creatorcontrib><creatorcontrib>Pugsley, Thomas A</creatorcontrib><creatorcontrib>Smith, Sarah J</creatorcontrib><creatorcontrib>Wise, Lawrence D</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>Animal Behavior Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Glase, Shelly A</au><au>Akunne, Hyacinth C</au><au>Heffner, Thomas G</au><au>Jaen, Juan C</au><au>MacKenzie, Robert G</au><au>Meltzer, Leonard T</au><au>Pugsley, Thomas A</au><au>Smith, Sarah J</au><au>Wise, Lawrence D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aryl 1-But-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as Potential Antipsychotic Agents: Synthesis and Structure−Activity Relationships</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1996-08-02</date><risdate>1996</risdate><volume>39</volume><issue>16</issue><spage>3179</spage><epage>3187</epage><pages>3179-3187</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure−activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8759640</pmid><doi>10.1021/jm950721m</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 1996-08, Vol.39 (16), p.3179-3187 |
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| source | ACS Publications; MEDLINE |
| subjects | Alkynes - chemical synthesis Alkynes - pharmacology Animals Antipsychotic Agents - chemical synthesis Antipsychotic Agents - chemistry Antipsychotic Agents - metabolism Antipsychotic Agents - pharmacology Binding, Competitive Biological and medical sciences Brain - drug effects Catecholaminergic system Dopamine - metabolism Dopamine Agents - chemical synthesis Dopamine Agents - chemistry Dopamine Agents - metabolism Dopamine Agents - pharmacology Humans Magnetic Resonance Spectroscopy Mass Spectrometry Medical sciences Mice Motor Activity - drug effects Neurons - drug effects Neurons - metabolism Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Pyridines - chemical synthesis Pyridines - chemistry Pyridines - metabolism Pyridines - pharmacology Rats Receptors, Dopamine D2 - metabolism Rodentia Saimiri Spiperone - metabolism Structure-Activity Relationship |
| title | Aryl 1-But-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as Potential Antipsychotic Agents: Synthesis and Structure−Activity Relationships |
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