Binding of the amphetamine-like 1-phenyl-piperazine to monoamine transporters

ACS Chem Neurosci. 2012 Sep 19;3(9):693-705. doi: 10.1021/cn300040f. Epub 2012 Jun 10.


The human serotonin transporter (hSERT), the human dopamine transporter (hDAT), and the human norepinephrine transporter (hNET) facilitate the active uptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Drugs of abuse such as MDMA (streetname "ecstasy") and certain 1-phenyl-piperazine (PP) analogs such as 1-(3-chlorophenyl)-piperazine (mCPP) elicit their stimulatory effect by elevating the synaptic concentration of serotonin by blocking or reversing the normal transport activity of hSERT. Recent data suggest that certain analogs of PP may be able to counteract the addictive effect of cocaine. Little is still known about the precise mechanism by which MDMA and PP analogs function at hSERT, hDAT, and hNET and even less is known about the specific protein-ligand interactions. In this study, we provide a comprehensive biochemical examination of a repertoire of PP analogs in hSERT, hDAT, and hNET. Combined with induced fit docking models and molecular dynamics simulations of PP and 1-(3-hydroxyphenyl)-piperazine (3-OH-PP) bound to hSERT and hDAT, we present detailed molecular insight into the promiscuous binding of PP analogs in the monoamine transporters. We find that PP analogs inhibit uptake as well as induce release in all three monoamine transporters. We also find that the selectivity of the PP analogs can be adjusted by carefully selecting substituents on the PP skeleton.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamines / chemistry
  • Amphetamines / metabolism*
  • Animals
  • Cluster Analysis
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Indicators and Reagents
  • Ligands
  • Male
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Piperazines / chemistry
  • Piperazines / metabolism*
  • Protein Conformation
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Substrate Specificity
  • Vesicular Monoamine Transport Proteins / genetics
  • Vesicular Monoamine Transport Proteins / metabolism*


  • Amphetamines
  • Dopamine Plasma Membrane Transport Proteins
  • Indicators and Reagents
  • Ligands
  • Norepinephrine Plasma Membrane Transport Proteins
  • Piperazines
  • Serotonin Plasma Membrane Transport Proteins
  • Vesicular Monoamine Transport Proteins
  • Serotonin