Specific targeting of peripheral serotonin 5-HT3 receptors. Synthesis, biological investigation, and structure-activity relationships

Elena Morelli, Sandra Gemma, Roberta Budriesi, Giuseppe Campiani, Ettore Novellino, Caterina Fattorusso, Bruno Catalanotti, Salvatore Sanna Coccone, Sindu Ros, Giuseppe Borrelli, Vinod Kumar, Marco Persico, Isabella Fiorini, Vito Nacci, Pierfranco Ioan, Alberto Chiarini, Michel Hamon, Alfredo Cagnotto, Tiziana Mennini, Claudia FracassoMilena Colovic, Silvio Caccia, Stefania Butini

Research output: Contribution to journalArticle

Abstract

The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT3 receptor (5-HT3R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT 3Rs. The potent 5-HT3R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT 3R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT3R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT3R in the modulation of cardiac parameters.

Original languageEnglish
Pages (from-to)3548-3562
Number of pages15
JournalJournal of Medicinal Chemistry
Volume52
Issue number11
DOIs
Publication statusPublished - Jun 11 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Morelli, E., Gemma, S., Budriesi, R., Campiani, G., Novellino, E., Fattorusso, C., Catalanotti, B., Coccone, S. S., Ros, S., Borrelli, G., Kumar, V., Persico, M., Fiorini, I., Nacci, V., Ioan, P., Chiarini, A., Hamon, M., Cagnotto, A., Mennini, T., ... Butini, S. (2009). Specific targeting of peripheral serotonin 5-HT3 receptors. Synthesis, biological investigation, and structure-activity relationships. Journal of Medicinal Chemistry, 52(11), 3548-3562. https://doi.org/10.1021/jm900018b