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

J Med Chem. 2009 Jun 11;52(11):3548-62. doi: 10.1021/jm900018b.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Baroreflex / drug effects
  • Chemical Phenomena
  • Female
  • Guinea Pigs
  • Heart / drug effects*
  • Heart Atria / drug effects
  • Heart Atria / metabolism
  • Male
  • Mice
  • Models, Molecular
  • Myocardium / metabolism*
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / pharmacokinetics
  • Quinoxalines / pharmacology*
  • Quipazine / analogs & derivatives
  • Quipazine / chemical synthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT3 / drug effects*
  • Receptors, Serotonin, 5-HT3 / metabolism*
  • Serotonin 5-HT3 Receptor Agonists
  • Structure-Activity Relationship

Substances

  • Pyrroles
  • Quinoxalines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Agonists
  • Quipazine