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

Bioorg Med Chem. 2009 Mar 15;17(6):2607-22. doi: 10.1016/j.bmc.2008.11.045. Epub 2008 Nov 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Humans
  • Indoles / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyrazines / chemical synthesis*
  • Pyrazines / metabolism
  • Pyrazines / pharmacology*
  • Radioligand Assay
  • Serotonin 5-HT4 Receptor Antagonists*
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacology*
  • Sulfonamides / metabolism


  • Indoles
  • Pyrazines
  • Serotonin 5-HT4 Receptor Antagonists
  • Serotonin Antagonists
  • Sulfonamides
  • GR 113808