R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects.

Abstract

Phenibut is clinically used anxiolytic, mood elevator and nootropic drug. R-phenibut is responsible for the pharmacological activity of racemic phenibut, and this activity correlates with its binding affinity for GABAB receptors. In contrast, S-phenibut does not bind to GABAB receptors. In this study, we assessed the binding affinities of R-phenibut, S-phenibut, baclofen and gabapentin (GBP) for the α2-δ subunit of the voltage-dependent calcium channel (VDCC) using a subunit-selective ligand, radiolabelled GBP. Binding experiments using rat brain membrane preparations revealed that the equilibrium dissociation constants (Kis) for R-phenibut, S-phenibut, baclofen and GBP were 23, 39, 156 and 0.05μM, respectively. In the pentylenetetrazole (PTZ)-induced seizure test, we found that at doses up to 100mg/kg, R-phenibut did not affect PTZ-induced seizures. The anti-nociceptive effects of R-phenibut were assessed using the formalin-induced paw-licking test and the chronic constriction injury (CCI) of the sciatic nerve model. Pre-treatment with R-phenibut dose-dependently decreased the nociceptive response during both phases of the test. The anti-nociceptive effects of R-phenibut in the formalin-induced paw-licking test were not blocked by the GABAB receptor-selective antagonist CGP35348. In addition, treatment with R- and S-phenibut alleviated the mechanical and thermal allodynia induced by CCI of the sciatic nerve. Our data suggest that the binding affinity of R-phenibut for the α2-δ subunit of the VDCC is 4 times higher than its affinity for the GABAB receptor. The anti-nociceptive effects of R-phenibut observed in the tests of formalin-induced paw licking and CCI of the sciatic nerve were associated with its effect on the α2-δ subunit of the VDCC rather than with its effects on GABAB receptors. In conclusion, our results provide experimental evidence for GBP-like, anti-nociceptive properties of R-phenibut, which might be used clinically to treat neuropathic pain disorders.

• Authors: Liga Zvejniece, Edijs Vavers, Baiba Svalbe, Grigory Veinberg, Kristina Rizhanova, Vilnis Liepins, Ivars Kalvinsh, Maija Dambrova
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 137 Pg. 23-9 (Oct 2015) ISSN: 1873-5177 [Electronic] United States
• PMID: 26234470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Amines
• Analgesics
• Calcium Channels
• Cyclohexanecarboxylic Acids
• voltage gated calcium channel subunit Ca alpha2delta-1, human
• gamma-Aminobutyric Acid
• Gabapentin
• 4-amino-3-phenylbutyric acid

Topics

• Amines (metabolism, pharmacology)
• Analgesics (metabolism, pharmacology)
• Animals
• Calcium Channels (metabolism)
• Cyclohexanecarboxylic Acids (metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Gabapentin
• Male
• Mice, Inbred ICR
• Pain Measurement (drug effects, methods)
• Protein Binding (physiology)
• Rats
• Rats, Wistar
• gamma-Aminobutyric Acid (analogs & derivatives, metabolism, pharmacology)