|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
6
|
|
pubmed:dateCreated |
2009-3-20
|
|
pubmed:abstractText |
Based on the definition of a 5-HT(4) receptor antagonist pharmacophore, a series of pyrrolo[1,2-a]thieno[3,2-e] and pyrrolo[1,2-a]thieno[2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT(4) receptors. The compounds were synthesized by substituting the chlorine atom of the pyrazine ring with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR113808 (1) as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) were affected by both the substituent on the aromatic ring and the substituent on the lateral piperidine chain. A methyl group on the tricyclic ring produced a marked increase in affinity while an N-propyl or N-butyl group gave compounds with nanomolar affinities. Among the most potent ligands, 34d was selected for further pharmacological studies and evaluated in vivo. This compound acts as an antagonist/weak partial agonist in COS-7 cells stably expressing the 5-HT(4(a)) receptor and is of great interest as a peripheral antinociceptive agent.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Mar
|
|
pubmed:issn |
1464-3391
|
|
pubmed:author |
pubmed-author:BoulouardMichelM,
pubmed-author:BureauRonanR,
pubmed-author:Butt-GueulleSabrinaS,
pubmed-author:DauphinFrançoisF,
pubmed-author:DaveuCyrilC,
pubmed-author:DuchatellePascalP,
pubmed-author:DumuisAlineA,
pubmed-author:Lelong-BoulouardVéroniqueV,
pubmed-author:LemaîtreStéphaneS,
pubmed-author:LepailleurAlbanA,
pubmed-author:Lezoualc'hFrankF,
pubmed-author:PfeifferBrunoB,
pubmed-author:RaultSylvainS
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
15
|
|
pubmed:volume |
17
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
2607-22
|
|
pubmed:dateRevised |
2010-11-18
|
|
pubmed:meshHeading |
pubmed-meshheading:19261477-Animals,
pubmed-meshheading:19261477-COS Cells,
pubmed-meshheading:19261477-Cercopithecus aethiops,
pubmed-meshheading:19261477-Humans,
pubmed-meshheading:19261477-Indoles,
pubmed-meshheading:19261477-Models, Molecular,
pubmed-meshheading:19261477-Molecular Structure,
pubmed-meshheading:19261477-Pyrazines,
pubmed-meshheading:19261477-Radioligand Assay,
pubmed-meshheading:19261477-Serotonin 5-HT4 Receptor Antagonists,
pubmed-meshheading:19261477-Serotonin Antagonists,
pubmed-meshheading:19261477-Sulfonamides
|
|
pubmed:year |
2009
|
|
pubmed:articleTitle |
Novel antagonists of serotonin-4 receptors: synthesis and biological evaluation of pyrrolothienopyrazines.
|
|
pubmed:affiliation |
Centre d'Etudes et de Recherche sur le Médicament de Normandie, Université de Caen, 1 rue Vaubénard, 14032 Caen Cedex, France.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|
