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

Background We report that R- and S-phenibut (β-phenyl-γ-aminobutyric acid) - derivatives of GABA - bind with an affinity of c.a. 90 μM 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.