Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands

Bioorg Med Chem. 2015 Jul 15;23(14):4000-12. doi: 10.1016/j.bmc.2015.01.017. Epub 2015 Jan 17.


The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common molecular template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compounds described herein incorporates a change to that chemical template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed critical for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compounds. Additionally, using mouse liver microsomes to evaluate CYP450-mediated phase I metabolism, we determined that novel 1,2,3-triazole-containing compounds modestly improves metabolic stability compared to amide-containing analogues. The 1,2,3-triazole moiety allows for the modular attachment of chemical subunit libraries using copper-catalyzed azide-alkyne cycloaddition click chemistry, increasing the range of chemical entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents.

Keywords: 1,2,3-Triazole; Bioisoteric replacement; Click chemistry; Dopamine D3 receptor; Metabolic stability; Structure–activity relationships.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Click Chemistry / methods*
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Evaluation, Preclinical / methods
  • Drug Stability
  • HEK293 Cells
  • Humans
  • Inactivation, Metabolic
  • Ligands
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Radioligand Assay
  • Receptors, Dopamine D3 / chemistry
  • Receptors, Dopamine D3 / metabolism*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship*
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology


  • Ligands
  • Receptors, Dopamine D3
  • Small Molecule Libraries
  • Triazoles
  • Cytochrome P-450 Enzyme System