Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D(2)-like receptors

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3753-6. doi: 10.1016/j.bmcl.2014.06.079. Epub 2014 Jul 3.


Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.

Keywords: Binding affinity; Bivalent ligands; D(2) receptor; D(3) receptor; D(4) receptor; Dopamine; GPCR dimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Haloperidol / chemical synthesis
  • Haloperidol / chemistry
  • Haloperidol / pharmacology*
  • Humans
  • Ligands
  • Molecular Structure
  • Receptors, Dopamine D2 / metabolism*
  • Structure-Activity Relationship


  • Ligands
  • Receptors, Dopamine D2
  • Haloperidol