Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

J Enzyme Inhib Med Chem. 2016;31(sup3):10-24. doi: 10.1080/14756366.2016.1198902. Epub 2016 Jun 29.

Abstract

A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4-21) were synthesized and evaluated for their serotonin (5-HT1A/5-HT7) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT1A, 5-HT7 and mixed 5-HT1A/5-HT7 receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.

Keywords: Depression; PDE; long-chain arylpiperazines; phosphodiesterase inhibitors; serotonin.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemical synthesis
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / pharmacology*
  • Antidepressive Agents / chemical synthesis
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Chromatography, Micellar Electrokinetic Capillary
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Motor Activity / drug effects*
  • Phosphoric Diester Hydrolases / metabolism
  • Purinones / chemical synthesis
  • Purinones / chemistry
  • Purinones / pharmacology*
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Serotonin / metabolism
  • Structure-Activity Relationship
  • Swimming

Substances

  • 1H-imidazo(2,1-f)purine-2,4(3H,8H)-dione
  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Imidazoles
  • Purinones
  • Receptors, Serotonin
  • serotonin 7 receptor
  • Receptor, Serotonin, 5-HT1A
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human