Pro-neurogenic, Memory-Enhancing and Anti-stress Effects of DF302, a Novel Fluorine Gamma-Carboline Derivative with Multi-target Mechanism of Action

Mol Neurobiol. 2018 Jan;55(1):335-349. doi: 10.1007/s12035-017-0745-6.


A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter-male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi-target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon.

Keywords: 5-HT6 receptor; AMPA receptor; Aggression; Alzheimer’s disease; Hippocampal plasticity; Multi-target mechanisms; Stress and depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbolines / administration & dosage*
  • Drug Delivery Systems / methods*
  • Fluorine Compounds / administration & dosage*
  • Fluorine Compounds / metabolism
  • Indoles / administration & dosage
  • Indoles / chemistry
  • Male
  • Memory / drug effects*
  • Memory / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neurogenesis / drug effects*
  • Neurogenesis / physiology
  • Rats
  • Receptors, Serotonin / metabolism
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / metabolism
  • Stress, Psychological / psychology


  • Carbolines
  • Fluorine Compounds
  • Indoles
  • Receptors, Serotonin
  • serotonin 6 receptor
  • gamma-carboline
  • latrepirdine