Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands. development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties

J Med Chem. 2005 May 19;48(10):3564-75. doi: 10.1021/jm0493461.


Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine(3) (5-HT(3)) receptor. Most of the new compounds show subnanomolar 5-HT(3) receptor affinity. Ester 6bc showing a picomolar K(i) value is one of the most potent 5-HT(3) receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT(3) receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT(3) receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT(3) receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Acridines / chemical synthesis*
  • Acridines / chemistry
  • Acridines / pharmacology
  • Animals
  • Binding Sites
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Cerebral Cortex / metabolism
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Computer Simulation
  • Humans
  • In Vitro Techniques
  • Ligands
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin, 5-HT3 / metabolism*
  • Structure-Activity Relationship
  • Thermodynamics


  • 3-methyl-2-(4-methyl-1-piperazinyl)-N-(7-((1,2,3,4-tetrahydroacridin-9-yl)amino)heptyl)quinoline-4-carboxamide
  • Acridines
  • Cholinesterase Inhibitors
  • Ligands
  • Piperazines
  • Quinolines
  • Receptors, Serotonin, 5-HT3
  • Acetylcholinesterase
  • Butyrylcholinesterase