Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands

Molecules. 2021 May 26;26(11):3182. doi: 10.3390/molecules26113182.


N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease.

Keywords: D2-like dopamine receptors; D3 dopamine receptor subtype; G-protein coupled receptor (GPCR); bitopic ligands; dopamine receptor subtype selective ligands.

MeSH terms

  • Animals
  • Benzamides / chemistry
  • Binding, Competitive
  • Dopamine Agonists / chemistry
  • Dopamine Antagonists / chemistry
  • Drug Design
  • Humans
  • Kinetics
  • Levodopa
  • Ligands
  • Male
  • Mice
  • Mice, Inbred DBA
  • Parkinson Disease / drug therapy
  • Piperazines / chemistry*
  • Protein Binding
  • Rats
  • Receptors, Dopamine D2 / chemistry*
  • Receptors, Dopamine D3 / chemistry*


  • Benzamides
  • Dopamine Agonists
  • Dopamine Antagonists
  • Ligands
  • Piperazines
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Levodopa
  • phenylpiperazine