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

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 [ 3H]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.