Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity
Astemizole, a H 1 R antagonist shows high affinity to the histamine H 1 receptor but only a moderate affinity to the histamine H 4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H 1 receptor and to increase affinity to the histamine H 4 receptor. Therefore,...
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| Veröffentlicht in: | Naunyn-Schmiedeberg's archives of pharmacology 2014-03, Vol.387 (3), p.235-250 |
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| creator | Wagner, Eva Wittmann, Hans-Joachim Elz, Sigurd Strasser, Andrea |
| description | Astemizole, a H
1
R antagonist shows high affinity to the histamine H
1
receptor but only a moderate affinity to the histamine H
4
receptor. This study aims to modify the astemizole to keep high affinity to the histamine H
1
receptor and to increase affinity to the histamine H
4
receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H
1
and H
4
receptors. The new compounds show affinity to the histamine H
1
receptor in the p
K
i
range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H
4
receptor was surprisingly rather low (p
K
i
from 4.4 to 5.6). Three representative compounds were docked into the histamine H
1
receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H
4
receptor, a H
1
/H
4
-pharmacophore hypothesis was developed. |
| doi_str_mv | 10.1007/s00210-013-0926-4 |
| format | Article |
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1
R antagonist shows high affinity to the histamine H
1
receptor but only a moderate affinity to the histamine H
4
receptor. This study aims to modify the astemizole to keep high affinity to the histamine H
1
receptor and to increase affinity to the histamine H
4
receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H
1
and H
4
receptors. The new compounds show affinity to the histamine H
1
receptor in the p
K
i
range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H
4
receptor was surprisingly rather low (p
K
i
from 4.4 to 5.6). Three representative compounds were docked into the histamine H
1
receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H
4
receptor, a H
1
/H
4
-pharmacophore hypothesis was developed.</description><identifier>ISSN: 0028-1298</identifier><identifier>EISSN: 1432-1912</identifier><identifier>DOI: 10.1007/s00210-013-0926-4</identifier><identifier>PMID: 24241585</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Astemizole - chemical synthesis ; Astemizole - chemistry ; Astemizole - pharmacology ; Biomedical and Life Sciences ; Biomedicine ; Female ; Guinea Pigs ; Histamine Antagonists - chemical synthesis ; Histamine Antagonists - chemistry ; Histamine Antagonists - pharmacology ; Histamine H1 Antagonists - chemical synthesis ; Histamine H1 Antagonists - chemistry ; Histamine H1 Antagonists - pharmacology ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Male ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Neurosciences ; Original Article ; Pharmacology/Toxicology ; Piperazines - chemical synthesis ; Piperazines - chemistry ; Piperazines - pharmacology ; Receptors, G-Protein-Coupled - drug effects ; Receptors, G-Protein-Coupled - metabolism ; Receptors, Histamine - drug effects ; Receptors, Histamine - metabolism ; Receptors, Histamine H1 - drug effects ; Receptors, Histamine H1 - metabolism ; Receptors, Histamine H4 ; Sf9 Cells ; Spodoptera</subject><ispartof>Naunyn-Schmiedeberg's archives of pharmacology, 2014-03, Vol.387 (3), p.235-250</ispartof><rights>Springer-Verlag Berlin Heidelberg 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2594-a1e9422c3e218f4a7c6f90ee84110a798aaa445e5201eadbc1297b74925670a93</citedby><cites>FETCH-LOGICAL-c2594-a1e9422c3e218f4a7c6f90ee84110a798aaa445e5201eadbc1297b74925670a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00210-013-0926-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00210-013-0926-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24241585$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wagner, Eva</creatorcontrib><creatorcontrib>Wittmann, Hans-Joachim</creatorcontrib><creatorcontrib>Elz, Sigurd</creatorcontrib><creatorcontrib>Strasser, Andrea</creatorcontrib><title>Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity</title><title>Naunyn-Schmiedeberg's archives of pharmacology</title><addtitle>Naunyn-Schmiedeberg's Arch Pharmacol</addtitle><addtitle>Naunyn Schmiedebergs Arch Pharmacol</addtitle><description>Astemizole, a H
1
R antagonist shows high affinity to the histamine H
1
receptor but only a moderate affinity to the histamine H
4
receptor. This study aims to modify the astemizole to keep high affinity to the histamine H
1
receptor and to increase affinity to the histamine H
4
receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H
1
and H
4
receptors. The new compounds show affinity to the histamine H
1
receptor in the p
K
i
range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H
4
receptor was surprisingly rather low (p
K
i
from 4.4 to 5.6). Three representative compounds were docked into the histamine H
1
receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H
4
receptor, a H
1
/H
4
-pharmacophore hypothesis was developed.</description><subject>Animals</subject><subject>Astemizole - chemical synthesis</subject><subject>Astemizole - chemistry</subject><subject>Astemizole - pharmacology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Female</subject><subject>Guinea Pigs</subject><subject>Histamine Antagonists - chemical synthesis</subject><subject>Histamine Antagonists - chemistry</subject><subject>Histamine Antagonists - pharmacology</subject><subject>Histamine H1 Antagonists - chemical synthesis</subject><subject>Histamine H1 Antagonists - chemistry</subject><subject>Histamine H1 Antagonists - pharmacology</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Male</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>Neurosciences</subject><subject>Original Article</subject><subject>Pharmacology/Toxicology</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacology</subject><subject>Receptors, G-Protein-Coupled - drug effects</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Receptors, Histamine - drug effects</subject><subject>Receptors, Histamine - metabolism</subject><subject>Receptors, Histamine H1 - drug effects</subject><subject>Receptors, Histamine H1 - metabolism</subject><subject>Receptors, Histamine H4</subject><subject>Sf9 Cells</subject><subject>Spodoptera</subject><issn>0028-1298</issn><issn>1432-1912</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM9u1DAQxi1ERZfCA3BBPnJxO-PYm-SIKsoiVaKH9mzNOpOuqyRe7KSiPfEQPCFPgqstiBOnkeb7I30_Id4hnCJAfZYBNIICrBS0eq3MC7FCU2mFLeqXYlXkRqFum2PxOuc7AFijta_EsTbaoG3sSny_2lEaycch3gZPg9yn2IeBZewl5ZnH8BgHVh2ncM-d9HHcx2XqsqRZzjuWu5BnGsPEcoOSpk5ujEzseT_H9OvHzw2e_fOQmQf2c7gP88MbcdTTkPnt8z0RNxefrs836vLr5y_nHy-V17Y1ipBbo7WvWGPTG6r9um-BuTGIQHXbEJExlq0GZOq2vsytt7VptV3XQG11Ij4cesuwbwvn2Y0hex4Gmjgu2aEtJAEqA8WKB6tPMefEvdunMFJ6cAjuCbg7AHcFuHsC7kzJvH-uX7Yjd38TfwgXgz4YcpGmW07uLi5pKpP_0_obK3-MOw</recordid><startdate>201403</startdate><enddate>201403</enddate><creator>Wagner, Eva</creator><creator>Wittmann, Hans-Joachim</creator><creator>Elz, Sigurd</creator><creator>Strasser, Andrea</creator><general>Springer Berlin Heidelberg</general><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>201403</creationdate><title>Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity</title><author>Wagner, Eva ; Wittmann, Hans-Joachim ; Elz, Sigurd ; Strasser, Andrea</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2594-a1e9422c3e218f4a7c6f90ee84110a798aaa445e5201eadbc1297b74925670a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Astemizole - chemical synthesis</topic><topic>Astemizole - chemistry</topic><topic>Astemizole - pharmacology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Female</topic><topic>Guinea Pigs</topic><topic>Histamine Antagonists - chemical synthesis</topic><topic>Histamine Antagonists - chemistry</topic><topic>Histamine Antagonists - pharmacology</topic><topic>Histamine H1 Antagonists - chemical synthesis</topic><topic>Histamine H1 Antagonists - chemistry</topic><topic>Histamine H1 Antagonists - pharmacology</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Male</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Dynamics Simulation</topic><topic>Neurosciences</topic><topic>Original Article</topic><topic>Pharmacology/Toxicology</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacology</topic><topic>Receptors, G-Protein-Coupled - drug effects</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Receptors, Histamine - drug effects</topic><topic>Receptors, Histamine - metabolism</topic><topic>Receptors, Histamine H1 - drug effects</topic><topic>Receptors, Histamine H1 - metabolism</topic><topic>Receptors, Histamine H4</topic><topic>Sf9 Cells</topic><topic>Spodoptera</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wagner, Eva</creatorcontrib><creatorcontrib>Wittmann, Hans-Joachim</creatorcontrib><creatorcontrib>Elz, Sigurd</creatorcontrib><creatorcontrib>Strasser, Andrea</creatorcontrib><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>Naunyn-Schmiedeberg's archives of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wagner, Eva</au><au>Wittmann, Hans-Joachim</au><au>Elz, Sigurd</au><au>Strasser, Andrea</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity</atitle><jtitle>Naunyn-Schmiedeberg's archives of pharmacology</jtitle><stitle>Naunyn-Schmiedeberg's Arch Pharmacol</stitle><addtitle>Naunyn Schmiedebergs Arch Pharmacol</addtitle><date>2014-03</date><risdate>2014</risdate><volume>387</volume><issue>3</issue><spage>235</spage><epage>250</epage><pages>235-250</pages><issn>0028-1298</issn><eissn>1432-1912</eissn><abstract>Astemizole, a H
1
R antagonist shows high affinity to the histamine H
1
receptor but only a moderate affinity to the histamine H
4
receptor. This study aims to modify the astemizole to keep high affinity to the histamine H
1
receptor and to increase affinity to the histamine H
4
receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H
1
and H
4
receptors. The new compounds show affinity to the histamine H
1
receptor in the p
K
i
range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H
4
receptor was surprisingly rather low (p
K
i
from 4.4 to 5.6). Three representative compounds were docked into the histamine H
1
receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H
4
receptor, a H
1
/H
4
-pharmacophore hypothesis was developed.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>24241585</pmid><doi>10.1007/s00210-013-0926-4</doi><tpages>16</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-1298 |
| ispartof | Naunyn-Schmiedeberg's archives of pharmacology, 2014-03, Vol.387 (3), p.235-250 |
| issn | 0028-1298 1432-1912 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1500700340 |
| source | MEDLINE; Springer Online Journals Complete |
| subjects | Animals Astemizole - chemical synthesis Astemizole - chemistry Astemizole - pharmacology Biomedical and Life Sciences Biomedicine Female Guinea Pigs Histamine Antagonists - chemical synthesis Histamine Antagonists - chemistry Histamine Antagonists - pharmacology Histamine H1 Antagonists - chemical synthesis Histamine H1 Antagonists - chemistry Histamine H1 Antagonists - pharmacology Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Male Molecular Docking Simulation Molecular Dynamics Simulation Neurosciences Original Article Pharmacology/Toxicology Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Receptors, G-Protein-Coupled - drug effects Receptors, G-Protein-Coupled - metabolism Receptors, Histamine - drug effects Receptors, Histamine - metabolism Receptors, Histamine H1 - drug effects Receptors, Histamine H1 - metabolism Receptors, Histamine H4 Sf9 Cells Spodoptera |
| title | Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity |
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