Optical isomers of phenibut inhibit [H(3)]-Gabapentin binding in vitro and show activity in animal models of chronic pain

Pharmacol Rep. 2016 Jun;68(3):550-4. doi: 10.1016/j.pharep.2015.12.004. Epub 2015 Dec 22.


Background: We report that R- and S-phenibut (β-phenyl-γ-aminobutyric acid) - derivatives of GABA - bind with an affinity of c.a. 90μM to the gabapentin binding site in a competitive assay, a value comparable to that for previously claimed targets for this enantioermic molecule. This finding implied potential activity in neuropathic pain, this being one of the clinically validated indications for gabapentin.

Methods: The effect of phenibut on tactile allodynia was tested in a chronic constriction nerve injury (CCI) neuropathic pain model and against hypersensitivity following inflammation induced by inoculation using complete Freund's adjuvant (CFA) model.

Results: Indeed, a significant inhibitory effect on tactile allodynia was detected in rats in both employed chronic pain models with stronger and clearly dose dependent effect with R isomer.

Conclusions: The results confirm activity in chronic pain models predicted from affinity for the gabapentin site and suggests, at least partially, that α2δ-subunits of presynaptic voltage-gated calcium channels are involved in mediating this effect.

Keywords: Chronic constriction nerve injury; Complete Freund's adjuvant; Gabapentin binding; Inflammatory pain; Neuropathic pain.

MeSH terms

  • Amines / antagonists & inhibitors*
  • Animals
  • Chronic Pain / drug therapy*
  • Cyclohexanecarboxylic Acids / antagonists & inhibitors*
  • Disease Models, Animal
  • Freund's Adjuvant
  • Gabapentin
  • Hypersensitivity / drug therapy
  • Male
  • Pain Measurement / drug effects
  • Radioligand Assay
  • Rats
  • Stereoisomerism
  • gamma-Aminobutyric Acid / analogs & derivatives*
  • gamma-Aminobutyric Acid / pharmacology
  • gamma-Aminobutyric Acid / therapeutic use


  • Amines
  • Cyclohexanecarboxylic Acids
  • gamma-Aminobutyric Acid
  • Gabapentin
  • Freund's Adjuvant
  • 4-amino-3-phenylbutyric acid