Synthesis, dopamine D2 receptor binding studies and docking analysis of 5-[3-(4-arylpiperazin-1-yl)propyl]-1H-benzimidazole, 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazole and their analogs

Eur J Med Chem. 2005 May;40(5):481-93. doi: 10.1016/j.ejmech.2004.10.006. Epub 2005 Apr 1.

Abstract

5-[3-(4-Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D1, D2 and 5-HT1A receptors examined. They expressed a rather high affinity for the D2 dopamine receptor. The main features of ligand-D2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-[2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy]-1,3-dihydro-2H-benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D2 receptor and competition binding results was observed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Binding, Competitive
  • Cattle
  • Caudate Nucleus / metabolism
  • Dopamine Agents / chemical synthesis*
  • Dopamine Agents / chemistry
  • Dopamine Agents / pharmacology
  • Dopamine D2 Receptor Antagonists
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Binding
  • Radioligand Assay
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Serotonin, 5-HT1 / metabolism
  • Serotonin 5-HT1 Receptor Antagonists
  • Spectrophotometry, Infrared

Substances

  • Benzimidazoles
  • Dopamine Agents
  • Dopamine D2 Receptor Antagonists
  • Piperazines
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Serotonin, 5-HT1
  • Serotonin 5-HT1 Receptor Antagonists