Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 1. Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives

J Med Chem. 1998 Feb 26;41(5):728-41. doi: 10.1021/jm970645i.


Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a Ki value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximately 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzene / chemistry
  • Binding Sites
  • Glioma
  • Guanidine / metabolism
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neuroblastoma
  • Phenanthridines / chemical synthesis
  • Phenanthridines / metabolism*
  • Phenanthridines / pharmacology
  • Piperazines / chemical synthesis
  • Piperazines / metabolism*
  • Piperazines / pharmacology
  • Quinolines / chemistry
  • Quipazine / chemistry
  • Quipazine / metabolism
  • Rats
  • Receptors, Serotonin / chemistry*
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / metabolism*
  • Serotonin Receptor Agonists / chemical synthesis
  • Serotonin Receptor Agonists / metabolism*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • 6-(4-methyl-1-piperazinyl)--7,8,9,10-tetrahydro-8,10-ethanophenanthridine
  • 6-(4-methyl-1-piperazinyl)-7,8,9,10-tetrahydrophenanthridine
  • Phenanthridines
  • Piperazines
  • Quinolines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Quipazine
  • quinoline
  • Benzene
  • Guanidine