Novel Benzo[b]quinolizinium Cations as Uncompetitive N-Methyl-D-aspartic Acid (NMDA) Antagonists: The Relationship between log D and Agonist Independent (Closed) NMDA Channel Block
A series of permanently charged benzo[b]quinolizinium cations having lower lipophilicity than MK-801 or phencyclidine (PCP) were synthesized. Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result i...
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| Veröffentlicht in: | Journal of medicinal chemistry 1995-09, Vol.38 (18), p.3586-3592 |
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| container_issue | 18 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 38 |
| creator | Earley, William G Kumar, Virendra Mallamo, John P Subramanyam, Chakrapani Dority, John A Miller, Matthew S DeHaven-Hudkins, Diane L Aimone, Lisa D Kelly, Michael D Ault, Brian |
| description | A series of permanently charged benzo[b]quinolizinium cations having lower lipophilicity than MK-801 or phencyclidine (PCP) were synthesized. Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result in a more noncompetitive profile of antagonism compared to selective open channel blockers, which are uncompetitive inhibitors. Reduced closed channel block may underlie the absence of PCP or MK-801-like behavioral side effects observed for benzo[b]-quinolizinium cations. |
| doi_str_mv | 10.1021/jm00018a018 |
| format | Article |
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Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result in a more noncompetitive profile of antagonism compared to selective open channel blockers, which are uncompetitive inhibitors. Reduced closed channel block may underlie the absence of PCP or MK-801-like behavioral side effects observed for benzo[b]-quinolizinium cations.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00018a018</identifier><identifier>PMID: 7658445</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Binding Sites ; Biological and medical sciences ; Cations ; Cells, Cultured ; Dizocilpine Maleate - analogs & derivatives ; Dizocilpine Maleate - chemistry ; Female ; Glutamatergic system (aspartate and other excitatory aminoacids) ; In Vitro Techniques ; Medical sciences ; Mice ; N-Methylaspartate - antagonists & inhibitors ; N-Methylaspartate - metabolism ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Oocytes - cytology ; Pharmacology. Drug treatments ; Phencyclidine - analogs & derivatives ; Phencyclidine - chemistry ; Quinolizines - chemistry ; Quinolizines - pharmacology ; Structure-Activity Relationship ; Xenopus laevis</subject><ispartof>Journal of medicinal chemistry, 1995-09, Vol.38 (18), p.3586-3592</ispartof><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a383t-812b326948589868b4bf75c04f4526c8c8e582f26e875e7602fface8ee97cffd3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00018a018$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00018a018$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3658930$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7658445$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Earley, William G</creatorcontrib><creatorcontrib>Kumar, Virendra</creatorcontrib><creatorcontrib>Mallamo, John P</creatorcontrib><creatorcontrib>Subramanyam, Chakrapani</creatorcontrib><creatorcontrib>Dority, John A</creatorcontrib><creatorcontrib>Miller, Matthew S</creatorcontrib><creatorcontrib>DeHaven-Hudkins, Diane L</creatorcontrib><creatorcontrib>Aimone, Lisa D</creatorcontrib><creatorcontrib>Kelly, Michael D</creatorcontrib><creatorcontrib>Ault, Brian</creatorcontrib><title>Novel Benzo[b]quinolizinium Cations as Uncompetitive N-Methyl-D-aspartic Acid (NMDA) Antagonists: The Relationship between log D and Agonist Independent (Closed) NMDA Channel Block</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of permanently charged benzo[b]quinolizinium cations having lower lipophilicity than MK-801 or phencyclidine (PCP) were synthesized. Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result in a more noncompetitive profile of antagonism compared to selective open channel blockers, which are uncompetitive inhibitors. Reduced closed channel block may underlie the absence of PCP or MK-801-like behavioral side effects observed for benzo[b]-quinolizinium cations.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cations</subject><subject>Cells, Cultured</subject><subject>Dizocilpine Maleate - analogs & derivatives</subject><subject>Dizocilpine Maleate - chemistry</subject><subject>Female</subject><subject>Glutamatergic system (aspartate and other excitatory aminoacids)</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>N-Methylaspartate - antagonists & inhibitors</subject><subject>N-Methylaspartate - metabolism</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Oocytes - cytology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phencyclidine - analogs & derivatives</subject><subject>Phencyclidine - chemistry</subject><subject>Quinolizines - chemistry</subject><subject>Quinolizines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Xenopus laevis</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0U1v1DAQBuAIgcrScuKM5AMqrVDAcb4cbtldKBXt8tHtBYQsx5l0vXXsNHYK7e_iB9arrFYcOHh8mEevRjNB8CLCbyNMonfrFmMcUe7fo2ASpQSHCcXJ42CCMSEhyUj8NHhm7dqzOCLxXrCXZylNknQS_F2YW1BoCvre_Kx-3QxSGyXvpZZDi2bcSaMt4hZdamHaDpx08hbQIjwHt7pT4TzktuO9kwKVQtboaHE-L49RqR2_MlpaZ9-j5QrQd1Bj1kp2qAL3G0AjZa7QHHFdo3LE6FTX0IEv2qGjmTIW6mO0iUSzFdd6M6gy4vogeNJwZeH59t8PLj9-WM4-hWdfTk5n5VnIYxq7kEakiklWJDSlBc1olVRNngqcNElKMkEFhZSShmRA8xTyDJOm4QIoQJGLpqnj_eBwzO16czOAdayVVoBSXIMZLMvzJC8wzTx8M0LRG2t7aFjXy5b3dyzCbHMj9s-NvH65jR2qFuqd3R7F919t-9wKrpqeayHtjsWeFTH2LByZ3xz82bV5f82yPM5Ttvx6wX5MTxbF9NsF--z969FzYdnaDL32u_vvgA9cA7Wp</recordid><startdate>19950901</startdate><enddate>19950901</enddate><creator>Earley, William G</creator><creator>Kumar, Virendra</creator><creator>Mallamo, John P</creator><creator>Subramanyam, Chakrapani</creator><creator>Dority, John A</creator><creator>Miller, Matthew S</creator><creator>DeHaven-Hudkins, Diane L</creator><creator>Aimone, Lisa D</creator><creator>Kelly, Michael D</creator><creator>Ault, Brian</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>19950901</creationdate><title>Novel Benzo[b]quinolizinium Cations as Uncompetitive N-Methyl-D-aspartic Acid (NMDA) Antagonists: The Relationship between log D and Agonist Independent (Closed) NMDA Channel Block</title><author>Earley, William G ; Kumar, Virendra ; Mallamo, John P ; Subramanyam, Chakrapani ; Dority, John A ; Miller, Matthew S ; DeHaven-Hudkins, Diane L ; Aimone, Lisa D ; Kelly, Michael D ; Ault, Brian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-812b326948589868b4bf75c04f4526c8c8e582f26e875e7602fface8ee97cffd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cations</topic><topic>Cells, Cultured</topic><topic>Dizocilpine Maleate - analogs & derivatives</topic><topic>Dizocilpine Maleate - chemistry</topic><topic>Female</topic><topic>Glutamatergic system (aspartate and other excitatory aminoacids)</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>N-Methylaspartate - antagonists & inhibitors</topic><topic>N-Methylaspartate - metabolism</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Oocytes - cytology</topic><topic>Pharmacology. Drug treatments</topic><topic>Phencyclidine - analogs & derivatives</topic><topic>Phencyclidine - chemistry</topic><topic>Quinolizines - chemistry</topic><topic>Quinolizines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Earley, William G</creatorcontrib><creatorcontrib>Kumar, Virendra</creatorcontrib><creatorcontrib>Mallamo, John P</creatorcontrib><creatorcontrib>Subramanyam, Chakrapani</creatorcontrib><creatorcontrib>Dority, John A</creatorcontrib><creatorcontrib>Miller, Matthew S</creatorcontrib><creatorcontrib>DeHaven-Hudkins, Diane L</creatorcontrib><creatorcontrib>Aimone, Lisa D</creatorcontrib><creatorcontrib>Kelly, Michael D</creatorcontrib><creatorcontrib>Ault, Brian</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>Earley, William G</au><au>Kumar, Virendra</au><au>Mallamo, John P</au><au>Subramanyam, Chakrapani</au><au>Dority, John A</au><au>Miller, Matthew S</au><au>DeHaven-Hudkins, Diane L</au><au>Aimone, Lisa D</au><au>Kelly, Michael D</au><au>Ault, Brian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Benzo[b]quinolizinium Cations as Uncompetitive N-Methyl-D-aspartic Acid (NMDA) Antagonists: The Relationship between log D and Agonist Independent (Closed) NMDA Channel Block</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1995-09-01</date><risdate>1995</risdate><volume>38</volume><issue>18</issue><spage>3586</spage><epage>3592</epage><pages>3586-3592</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of permanently charged benzo[b]quinolizinium cations having lower lipophilicity than MK-801 or phencyclidine (PCP) were synthesized. Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result in a more noncompetitive profile of antagonism compared to selective open channel blockers, which are uncompetitive inhibitors. Reduced closed channel block may underlie the absence of PCP or MK-801-like behavioral side effects observed for benzo[b]-quinolizinium cations.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>7658445</pmid><doi>10.1021/jm00018a018</doi><tpages>7</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1995-09, Vol.38 (18), p.3586-3592 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Binding Sites Biological and medical sciences Cations Cells, Cultured Dizocilpine Maleate - analogs & derivatives Dizocilpine Maleate - chemistry Female Glutamatergic system (aspartate and other excitatory aminoacids) In Vitro Techniques Medical sciences Mice N-Methylaspartate - antagonists & inhibitors N-Methylaspartate - metabolism Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Oocytes - cytology Pharmacology. Drug treatments Phencyclidine - analogs & derivatives Phencyclidine - chemistry Quinolizines - chemistry Quinolizines - pharmacology Structure-Activity Relationship Xenopus laevis |
| title | Novel Benzo[b]quinolizinium Cations as Uncompetitive N-Methyl-D-aspartic Acid (NMDA) Antagonists: The Relationship between log D and Agonist Independent (Closed) NMDA Channel Block |
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