Novel antagonists of serotonin-4 receptors: Synthesis and biological evaluation of pyrrolothienopyrazines |
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Authors: | Stéphane Lemaître Alban Lepailleur Ronan Bureau Sabrina Butt-Gueulle Véronique Lelong-Boulouard Pascal Duchatelle Michel Boulouard Aline Dumuis Cyril Daveu Frank Lezoualc’h Bruno Pfeiffer François Dauphin Sylvain Rault |
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Institution: | 1. Centre d’Etudes et de Recherche sur le Médicament de Normandie, Université de Caen, 1 rue Vaubénard, 14032 Caen Cedex, France;2. UPR 9023, CCIPE, 141 rue de la Cardonille, 34094 Montpellier Cedex 5, France;3. INSERM U769, University Paris XI, IFR141, 5 rue JB Clément, 92296 Châtenay-Malabry, France;4. Les Laboratoires Servier 1, rue Carle Hebert 92415 Courbevoie Cedex, France |
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Abstract: | Based on the definition of a 5-HT4 receptor antagonist pharmacophore, a series of pyrrolo1,2-a]thieno3,2-e] and pyrrolo1,2-a]thieno2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT4 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 3H]GR113808 (1) as the 5-HT4 receptor radioligand. The affinity values (Ki 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-HT4(a) receptor and is of great interest as a peripheral antinociceptive agent. |
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