Hintersteiner Juliane, Haider Maximilian, Luger Denise, Schwarzer Christoph, Reznicek Gottfried, Jäger Walter, Khom Sophia, Mihovilovic Marko D, Hering Steffen
Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria.
Eur J Pharmacol. 2014 Jul 15;735(100):123-31. doi: 10.1016/j.ejphar.2014.03.019. Epub 2014 Mar 27.
Valerenic acid (VA) is a β2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABAA) receptors inducing anxiolysis. Here we analyze if VA-esters can serve as prodrugs and if different ester structures have different in vitro/in vivo effects. Modulation of GABAA receptors expressed in Xenopus oocytes was studied with 2-microelectrode-voltage-clamp. Anxiolytic effects of the VA-esters were studied on male C57BL/6N mice by means of the elevated plus maze-test; anticonvulsant properties were deduced from changes in seizure threshold upon pentylenetetrazole infusion. VA was detected in plasma confirming hydrolysis of the esters and release of VA in vivo. Esterification significantly reduced the positive allosteric modulation of GABAA (α1β3γ2S) receptors in vitro. in vivo, the studied VA-ester derivatives induced similar or even stronger anxiolytic and anticonvulsant action than VA. While methylation and propylation of VA resulted in faster onset of anxiolysis, the action of VA-ethylester was longer lasting, but occurred with a significant delay. The later finding is in line with the longer lasting anticonvulsant effects of this compound. The estimated VA plasma concentrations provided first insight into the release kinetics from different VA-esters. This might be an important step for its future clinical application as a potential non-sedative anxiolytic and anticonvulsant.
缬草烯酸（VA）是一种γ-氨基丁酸（GABA）A型（GABAA）受体的β2/3亚基特异性调节剂，具有抗焦虑作用。在此，我们分析VA酯是否可作为前药，以及不同的酯结构是否具有不同的体外/体内效应。利用双微电极电压钳研究了非洲爪蟾卵母细胞中表达的GABAA受体的调节情况。通过高架十字迷宫试验研究了VA酯对雄性C57BL/6N小鼠的抗焦虑作用；通过注入戊四氮后癫痫阈值的变化推断其抗惊厥特性。在血浆中检测到了VA，证实了酯的水解以及VA在体内的释放。酯化作用在体外显著降低了GABAA（α1β3γ2S）受体的正向变构调节作用。在体内，所研究的VA酯衍生物诱导出的抗焦虑和抗惊厥作用与VA相似甚至更强。虽然VA的甲基化和丙基化导致抗焦虑作用起效更快，但VA乙酯的作用持续时间更长，但出现明显延迟。后一发现与该化合物更持久的抗惊厥作用一致。估计的VA血浆浓度首次揭示了不同VA酯的释放动力学。这可能是其未来作为潜在的非镇静性抗焦虑和抗惊厥药物临床应用的重要一步。
