Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives

Eur J Med Chem. 2009 Nov;44(11):4288-96. doi: 10.1016/j.ejmech.2009.07.014. Epub 2009 Jul 21.

Abstract

A series of N-8-arylpiperazinylpropyl derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2-10) and amide derivatives of 1,3-dimethyl-6,7-dihydroimidazo[2,1-f]purine-2,4-(1H,3H)-dione-7-carboxylic acid (11-13) were synthesized. Compounds (2-10) evaluated in vitro were potent 5-HT(1A) receptor ligands. Preclinical studies indicated that 8-[3-(N4-phenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2) exerts anxiolytic-like activity in the four-plate test in mice; however its effect was weaker, than that produced by Diazepam. This compound and 8-[3-(N4-2'-metoxyphenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (3) behaved like antidepressants in the forced swimming test in mice; and their activity in that model was comparable with the effect of Imipramine. The obtained results suggested that the long-chain arylpiperazines (LCAPs) linked to tricyclic derivatives of the theophylline remain a worthy of future research for obtaining new derivatives with potential anxiolytic/antidepressant activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / therapeutic use*
  • Body Temperature / drug effects
  • Cerebral Cortex / metabolism
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / therapeutic use
  • Male
  • Mice
  • Molecular Structure
  • Motor Activity / drug effects
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Binding
  • Purines / chemical synthesis*
  • Purines / chemistry
  • Purines / therapeutic use*
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Theophylline / analogs & derivatives*

Substances

  • Antidepressive Agents
  • Imidazoles
  • Piperazines
  • Purines
  • Receptors, Dopamine D2
  • Receptor, Serotonin, 5-HT1A
  • Theophylline