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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >R-phenibut binds to the alpha(2)-delta subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects
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R-phenibut binds to the alpha(2)-delta subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects

机译：R-phenibut绑定到电压依赖性钙通道的alpha（2）-delta亚基，并发挥加巴喷丁样抗伤害作用

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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 GABA(B) 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 alpha(2)-delta 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 (K(i)s) for R-phenibut, S-phenibut, baclofen and GBP were 23, 39, 156 and 0.05 mu M, respectively. In the pentylenetetrazole (PTZ)-induced seizure test, we found that at doses up to 100 mg/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 alpha(2)-delta 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 alpha(2)-delta 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. (C) 2015 Elsevier Inc. All rights reserved.
机译：Phenibut是临床上使用的抗焦虑药，情绪提升药和促智药。 R-phenibut负责外消旋phenibut的药理活性，该活性与其对GABA（B）受体的结合亲和力有关。相比之下，S-苯乙但是不与GABAB受体结合。在这项研究中，我们使用亚基选择性配体评估了R-phenibut，S-phenibut，baclofen和gabapentin（GBP）对电压依赖性钙通道（VDCC）的alpha（2）-δ亚基的结合亲和力，放射性标记的GBP。使用大鼠脑膜制剂的结合实验表明，R-苯丁酸，S-苯丁酸，巴氯芬和GBP的平衡解离常数（K（i）s）分别为23、39、156和0.05μM。在戊烯四唑（PTZ）诱发的癫痫发作试验中，我们发现，在高达100 mg / kg的剂量下，R-苯尼丁不影响PTZ诱发的癫痫发作。使用福尔马林诱导的爪舔试验和坐骨神经模型的慢性压迫性损伤（CCI）评估了R-phenibut的抗伤害感受作用。在测试的两个阶段中，用R-苯丁酸进行的剂量依赖性地降低伤害性反应。 GABAB受体选择性拮抗剂CGP35348并未阻止福尔马林诱导的舔爪试验中R-苯丁酸的镇痛作用。此外，用R-和S-苯乙酮治疗可减轻坐骨神经CCI引起的机械性和热性异常性疼痛。我们的数据表明，R-phenibut对VDCC的alpha（2）-delta亚基的结合亲和力比其对GABAB受体的亲和力高4倍。在福尔马林诱导的爪舔和坐骨神经CCI测试中观察到的R-苯丁酸具有抗伤害感受作用，与其对VDCC的alpha（2）-δ亚基的作用有关，而不是对GABAB受体的影响。总之，我们的结果为R-苯丁酸类GBP的抗伤害感受特性提供了实验证据，可在临床上用于治疗神经性疼痛疾病。 （C）2015 Elsevier Inc.保留所有权利。

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