Bivalent molecular probes for dopamine D2-like receptors

Bioorg Med Chem. 2012 Jan 1;20(1):455-66. doi: 10.1016/j.bmc.2011.10.063. Epub 2011 Oct 25.


Merging two arylamidoalkyl substituted phenylpiperazines as prototypical recognition elements for dopamine D(2)-like receptors by oligoethylene glycol linkers led to a series of bivalent ligands. These dimers were investigated in comparison to their monomeric analogues for their dopamine D(2long), D(2short), D(3) and D(4) receptor binding. Radioligand binding experiments revealed strong bivalent effects for some para-substituted benzamide derivatives. For the D(3) subtype, the target compounds 32, 34 and 36 showed an up to 70-fold increase of affinity and a substantial enhancement of subtype selectivity when compared to the monovalent analogue 24. Analysis of the binding curves displayed Hill slopes very close to one indicating that the bivalent ligands displace 1equiv of radioligand. Obviously, the two pharmacophores occupy an orthosteric and an allosteric binding site rather than adopting a receptor-bridging binding mode.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Dopamine D2 Receptor Antagonists
  • Ethylene Glycol / chemistry
  • Isotope Labeling
  • Ligands
  • Molecular Probes / chemistry*
  • Molecular Probes / metabolism
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Protein Binding
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3 / antagonists & inhibitors
  • Receptors, Dopamine D3 / metabolism
  • Receptors, Dopamine D4 / antagonists & inhibitors
  • Receptors, Dopamine D4 / metabolism


  • 4-(2-ethoxyethoxymethyl)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide
  • Benzamides
  • Dopamine D2 Receptor Antagonists
  • Ligands
  • Molecular Probes
  • Piperazines
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Receptors, Dopamine D4
  • Ethylene Glycol
  • phenylpiperazine