Bioorganic & Medicinal Chemistry 2009-03-15

Novel antagonists of serotonin-4 receptors: synthesis and biological evaluation of pyrrolothienopyrazines.

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

Index: Bioorg. Med. Chem. 17 , 2607-2622, (2009)

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Abstract

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.