title: 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.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia. Electronic address: liga@biomed.lu.lv.
authors.forename: Liga
authors.initials: L
authors.lastname: Zvejniece
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia; Riga Stradins University, Dzirciema 16, Riga, LV-1007, Latvia.
authors.forename: Edijs
authors.initials: E
authors.lastname: Vavers
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia.
authors.forename: Baiba
authors.initials: B
authors.lastname: Svalbe
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia.
authors.forename: Grigory
authors.initials: G
authors.lastname: Veinberg
authors.affiliation: JSC Olain Farm, Rupnicu 5, Olaine, LV-2114, Latvia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Rizhanova
authors.affiliation: JSC Olain Farm, Rupnicu 5, Olaine, LV-2114, Latvia.
authors.forename: Vilnis
authors.initials: V
authors.lastname: Liepins
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia.
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia; Riga Stradins University, Dzirciema 16, Riga, LV-1007, Latvia.
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000588:Amines / Q000378:metabolism* / Q000494:pharmacology; D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D008297:Male; D008813:Mice, Inbred ICR; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000588:Amines; D000700:Analgesics; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; C494035:voltage gated calcium channel subunit Ca alpha2delta-1, human; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C008842:4-amino-3-phenylbutyric acid
keywords: CCI of the sciatic nerve; CGP35348; Formalin-induced paw-licking test; Gabapentin; R-phenibut; The α(2)-δ subunit of the voltage-dependent calcium channel