Khom S, Hintersteiner J, Luger D, Haider M, Pototschnig G, Mihovilovic M D, Schwarzer C, Hering S
Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (S.K., J.H., D.L., S.H.); Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria (M.H., G.P., M.D.M.); and Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (C.S.)
Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (S.K., J.H., D.L., S.H.); Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria (M.H., G.P., M.D.M.); and Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (C.S.).
J Pharmacol Exp Ther. 2016 Jun;357(3):580-90. doi: 10.1124/jpet.116.232983. Epub 2016 Apr 18.
Valerenic acid (VA)-a β2/3-selective GABA type A (GABAA) receptor modulator-displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA's methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas impairment of locomotion was observed at doses ≥10 mg/kg.
缬草烯酸（VA）——一种β2/3选择性γ-氨基丁酸A型（GABAA）受体调节剂——在小鼠中表现出抗焦虑和抗惊厥作用，且无镇静作用，这使得VA成为一种有吸引力的候选药物。在此，我们通过一系列VA衍生物分析了β亚基依赖性增强γ-氨基丁酸诱导的氯离子电流（IGABA）的情况，并研究了它们对戊四氮（PTZ）诱导的癫痫阈值和运动的影响。在表达α1β1γ2S、α1β2γ2S或α1β3γ2S受体的卵母细胞中测定化合物诱导的IGABA增强情况。使用C57BL/6N小鼠研究对癫痫阈值和运动的影响，并与生理盐水处理的对照组进行比较。β2/3选择性VA衍生物，如VA-酰胺（VA-A），对α1β3γ2S受体（VA-A：最大效应Emax = 972 ± 69%，n = 6，P < 0.05）和α1β2γ2S受体（Emax = 1119 ± 72%，n = 6，P < 0.05）的调节作用比VA更有效（α1β3γ2S：VA：Emax = 632 ± 88%，n = 9；α1β2γ2S：VA：Emax = 721 ± 68%，n = 6），其癫痫阈值升高比VA更显著（生理盐水对照组：40.4 ± 1.4 mg/kg PTZ；VA 10 mg/kg：49.0 ± 1.8 mg/kg PTZ；VA-A 3 mg/kg：57.9 ± 1.9 mg/kg PTZ，P < 0.05）。同样，VA的甲酰胺（VA-MA）通过含β3受体增强IGABA的作用比VA更有效（Emax = 1043 ± 57%，P < 0.01，n = 6），表现出更强的抗惊厥作用。与VA相比，VA-四唑在较低剂量下增强IGABA的效力和抗惊厥作用增加（α1β3γ2S：VA-TET：半数有效浓度EC50 = 6.0 ± 1.0 μM，P < 0.05；VA-TET：0.3 mg/kg：47.3 ± 0.5 mg/kg PTZ；VA：10 mg/kg：49.0 ± 1.8 mg/kg PTZ，P < 0.05）。在较高剂量（≥10 mg/kg）时，VA-A、VA-MA和VA-TET会降低运动。相比之下，非选择性VA衍生物仅在高剂量（30 mg/kg）时诱导抗惊厥作用，或未表现出任何行为效应。我们的数据表明，β2/3选择性化合物VA-A、VA-MA和VA-TET在低剂量（≤10 mg/kg）时诱导抗惊厥作用，而在剂量≥10 mg/kg时观察到运动受损。
Zotero 插件
