N-(4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl)arylcarboxamides as novel dopamine D(3) receptor antagonists

Bioorg Med Chem Lett. 2003 Jul 7;13(13):2179-83. doi: 10.1016/s0960-894x(03)00389-5.


The dopamine D(3) receptor subtype has been targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. Previous synthetic studies provided structural requirements for high affinity binding to D(3) receptors which included a 2,3-dichloro-phenylpiperazine linked to an arylamido function via a butyl chain. To reduce lipophilicity of these agents and further investigate optimal conformation, a second series of 15 novel ligands was designed that included heteroaromatic substitution and unsaturated alkyl linkers. These compounds were synthesized and evaluated for binding at rat D(3) and D(2) receptors stably expressed in Sf9 cells. D(3) binding affinities ranged from K(i)=0.6-1080 nM, with a broad range of D(3)/D(2) selectivities (2-97). The discovery of potent, selective and bioavailable D(3) receptor ligands will provide essential molecular probes to elucidate the role D(3) receptors play in the psychomotor stimulant and reinforcing effects of cocaine.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Butanes / chemical synthesis*
  • Butanes / pharmacology*
  • CHO Cells
  • Chemical Phenomena
  • Chemistry, Physical
  • Cricetinae
  • Dopamine Antagonists / chemical synthesis*
  • Dopamine Antagonists / pharmacology*
  • Dopamine D2 Receptor Antagonists*
  • Humans
  • Indicators and Reagents
  • Molecular Conformation
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology*
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D3
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transfection


  • Butanes
  • DRD3 protein, human
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Indicators and Reagents
  • Piperazines
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3