Document Report Card

ID: ALA1136924

Journal: J Med Chem

Title: Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structure-activity relationships.

Authors: Morelli E, Gemma S, Budriesi R, Campiani G, Novellino E, Fattorusso C, Catalanotti B, Coccone SS, Ros S, Borrelli G, Persico M, Fiorini I, Nacci V, Ioan P, Chiarini A, Hamon M, Cagnotto A, Mennini T, Fracasso C, Colovic M, Caccia S, Butini S.

Abstract: The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R 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(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R 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-HT(3)R in the modulation of cardiac parameters.

CiteXplore: 19425598

DOI: 10.1021/jm900018b