Design and synthesis of promiscuous high-affinity monoamine transporter ligands: unraveling transporter selectivity

J Med Chem. 2006 Mar 9;49(5):1766-72. doi: 10.1021/jm050766f.

Abstract

A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-piperidines and 4-[2-[(bisphenyl)methoxy]ethyl]-piperidines with different types of substituents in the phenylpropyl side-chain were synthesized and examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). All of the compounds showed high binding affinities for the DAT in the low to subnanomolar range. Their ability to bind to the SERT and the NET, while maintaining their high affinity for the DAT, could be altered by substitution in positions C2 and C3 of the phenylpropyl side-chain. This approach gave rise to a new set of compounds with selectivity for the DAT, the DAT and the SERT, or the DAT and the NET. Six compounds (7, 9, 11, 12, 14, and 20) with relatively low SERT/DAT ratios were selected for additional study in biogenic amine uptake inhibition assays based on the biogenic amine transporter binding results. Some of the new ligands can serve as pharmacological tools to block DAT or DAT and another transporter simultaneously.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adrenergic Uptake Inhibitors / chemical synthesis
  • Adrenergic Uptake Inhibitors / chemistry
  • Adrenergic Uptake Inhibitors / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Dopamine Uptake Inhibitors / chemical synthesis
  • Dopamine Uptake Inhibitors / chemistry
  • Dopamine Uptake Inhibitors / pharmacology
  • Ligands
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism*
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Radioligand Assay
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Serotonin Uptake Inhibitors / chemical synthesis
  • Serotonin Uptake Inhibitors / chemistry
  • Serotonin Uptake Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adrenergic Uptake Inhibitors
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Ligands
  • Norepinephrine Plasma Membrane Transport Proteins
  • Piperidines
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors