1,2,5-Thiadiazole Analogues of Aceclidine as Potent m1 Muscarinic Agonists
The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 1...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-01, Vol.41 (3), p.379-392 |
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| creator | Ward, John S Merritt, Leander Calligaro, David O Bymaster, Franklin P Shannon, Harlan E Mitch, Charles H Whitesitt, Celia Brunsting, David Sheardown, Malcolm J Olesen, Preben H Swedberg, Michael D. B Jeppesen, Lone Sauerberg, Per |
| description | The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-π-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure−activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated. |
| doi_str_mv | 10.1021/jm970125n |
| format | Article |
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B ; Jeppesen, Lone ; Sauerberg, Per</creator><creatorcontrib>Ward, John S ; Merritt, Leander ; Calligaro, David O ; Bymaster, Franklin P ; Shannon, Harlan E ; Mitch, Charles H ; Whitesitt, Celia ; Brunsting, David ; Sheardown, Malcolm J ; Olesen, Preben H ; Swedberg, Michael D. B ; Jeppesen, Lone ; Sauerberg, Per</creatorcontrib><description>The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-π-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure−activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970125n</identifier><identifier>PMID: 9464368</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Brain - metabolism ; Cell Line ; Cholinergic system ; Hydrolysis ; Male ; Medical sciences ; Mice ; Models, Molecular ; Muscarinic Agonists - chemistry ; Muscarinic Agonists - metabolism ; Muscarinic Agonists - pharmacology ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Phosphatidylinositols - metabolism ; Quinuclidines - chemistry ; Quinuclidines - metabolism ; Quinuclidines - pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Static Electricity ; Thiadiazoles - chemistry</subject><ispartof>Journal of medicinal chemistry, 1998-01, Vol.41 (3), p.379-392</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm970125n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm970125n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2134651$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9464368$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ward, John S</creatorcontrib><creatorcontrib>Merritt, Leander</creatorcontrib><creatorcontrib>Calligaro, David O</creatorcontrib><creatorcontrib>Bymaster, Franklin P</creatorcontrib><creatorcontrib>Shannon, Harlan E</creatorcontrib><creatorcontrib>Mitch, Charles H</creatorcontrib><creatorcontrib>Whitesitt, Celia</creatorcontrib><creatorcontrib>Brunsting, David</creatorcontrib><creatorcontrib>Sheardown, Malcolm J</creatorcontrib><creatorcontrib>Olesen, Preben H</creatorcontrib><creatorcontrib>Swedberg, Michael D. B</creatorcontrib><creatorcontrib>Jeppesen, Lone</creatorcontrib><creatorcontrib>Sauerberg, Per</creatorcontrib><title>1,2,5-Thiadiazole Analogues of Aceclidine as Potent m1 Muscarinic Agonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-π-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure−activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Cell Line</subject><subject>Cholinergic system</subject><subject>Hydrolysis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Muscarinic Agonists - chemistry</subject><subject>Muscarinic Agonists - metabolism</subject><subject>Muscarinic Agonists - pharmacology</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphatidylinositols - metabolism</subject><subject>Quinuclidines - chemistry</subject><subject>Quinuclidines - metabolism</subject><subject>Quinuclidines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Static Electricity</subject><subject>Thiadiazoles - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kctOwzAQRS0EKqWw4AOQsgBWDfgVO1lWhfJQKypRQGJjTWwHXPIocSIBX0-qVtUsZnGPZubOReiU4CuCKbleFonEhEblHuqTiOKQx5jvoz7GlIZUUHaIjrxfYowZoayHegkXnIm4jx7JkA6jcPHpwDj4q3IbjErIq4_W-qDKgpG2OnfGlTYAH8yrxpZNUJBg1noNtSudDkYfVel844_RQQa5tyfbPkAvk9vF-D6cPt09jEfTECjFTWgSzVKuBbUmSSLACYuBWQ5Ryk3GsNTSpKkxljISMStlBtrELBNGcm5iQdgAXW7mrurquzuzUYXz2uY5lLZqvZKJiNm6BuhsC7ZpYY1a1a6A-ldtzXf6-VaHzkye1VBq53cYJYyLaL0v3GCdSfuzk6H-UkIyGanF_Fm9z2evb_JmonDHX2x40F4tq7bu_ukVwWodldpFxf4BRNKBXA</recordid><startdate>19980129</startdate><enddate>19980129</enddate><creator>Ward, John S</creator><creator>Merritt, Leander</creator><creator>Calligaro, David O</creator><creator>Bymaster, Franklin P</creator><creator>Shannon, Harlan E</creator><creator>Mitch, Charles H</creator><creator>Whitesitt, Celia</creator><creator>Brunsting, David</creator><creator>Sheardown, Malcolm J</creator><creator>Olesen, Preben H</creator><creator>Swedberg, Michael D. 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Drug treatments</topic><topic>Phosphatidylinositols - metabolism</topic><topic>Quinuclidines - chemistry</topic><topic>Quinuclidines - metabolism</topic><topic>Quinuclidines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Static Electricity</topic><topic>Thiadiazoles - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ward, John S</creatorcontrib><creatorcontrib>Merritt, Leander</creatorcontrib><creatorcontrib>Calligaro, David O</creatorcontrib><creatorcontrib>Bymaster, Franklin P</creatorcontrib><creatorcontrib>Shannon, Harlan E</creatorcontrib><creatorcontrib>Mitch, Charles H</creatorcontrib><creatorcontrib>Whitesitt, Celia</creatorcontrib><creatorcontrib>Brunsting, David</creatorcontrib><creatorcontrib>Sheardown, Malcolm J</creatorcontrib><creatorcontrib>Olesen, Preben H</creatorcontrib><creatorcontrib>Swedberg, Michael D. B</creatorcontrib><creatorcontrib>Jeppesen, Lone</creatorcontrib><creatorcontrib>Sauerberg, Per</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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ward, John S</au><au>Merritt, Leander</au><au>Calligaro, David O</au><au>Bymaster, Franklin P</au><au>Shannon, Harlan E</au><au>Mitch, Charles H</au><au>Whitesitt, Celia</au><au>Brunsting, David</au><au>Sheardown, Malcolm J</au><au>Olesen, Preben H</au><au>Swedberg, Michael D. B</au><au>Jeppesen, Lone</au><au>Sauerberg, Per</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1,2,5-Thiadiazole Analogues of Aceclidine as Potent m1 Muscarinic Agonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-01-29</date><risdate>1998</risdate><volume>41</volume><issue>3</issue><spage>379</spage><epage>392</epage><pages>379-392</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-π-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure−activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9464368</pmid><doi>10.1021/jm970125n</doi><tpages>14</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1998-01, Vol.41 (3), p.379-392 |
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| subjects | Animals Biological and medical sciences Brain - metabolism Cell Line Cholinergic system Hydrolysis Male Medical sciences Mice Models, Molecular Muscarinic Agonists - chemistry Muscarinic Agonists - metabolism Muscarinic Agonists - pharmacology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Phosphatidylinositols - metabolism Quinuclidines - chemistry Quinuclidines - metabolism Quinuclidines - pharmacology Radioligand Assay Rats Rats, Sprague-Dawley Static Electricity Thiadiazoles - chemistry |
| title | 1,2,5-Thiadiazole Analogues of Aceclidine as Potent m1 Muscarinic Agonists |
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