Rycek Lukas, Puthenkalam Roshan, Schnürch Michael, Ernst Margot, Mihovilovic Marko D
Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria.
Medical University of Vienna, Department of Molecular Neurosciences, Spitalgasse 4, 1090 Vienna, Austria.
Bioorg Med Chem Lett. 2015 Jan 15;25(2):400-3. doi: 10.1016/j.bmcl.2014.10.091. Epub 2014 Nov 4.
We present the synthesis of new derivatives of natural products magnolol (1) and honokiol (2) and their evaluation as allosteric ligands for modulation of GABAA receptor activity. New derivatives were prepared via metal assisted cross-coupling reactions in two consecutive steps. Compounds were tested by means of two-electrode voltage clamp electrophysiology at the α1β2γ2 receptor subtype at low GABA concentrations. We have identified several compounds enhancing GABA induced current (IGABA) in the range similar or even higher than the lead structures. At 3μM, compound 8g enhanced IGABA by factor of 443, compared to 162 and 338 of honokiol and magnolol, respectively. Furthermore, 8g at EC10-20 features a much bigger window of separation between the α1β2γ2 and the α1β1γ2 subtypes compared to honokiol, and thus improved subtype selectivity.
我们展示了天然产物厚朴酚（1）和和厚朴酚（2）新衍生物的合成及其作为变构配体调节GABAA受体活性的评估。新衍生物通过连续两步的金属辅助交叉偶联反应制备。在低GABA浓度下，通过双电极电压钳电生理在α1β2γ2受体亚型上对化合物进行测试。我们已经鉴定出几种化合物增强GABA诱导电流（IGABA）的幅度与先导结构相似甚至更高。在3μM时，化合物8g使IGABA增强了443倍，相比之下，和厚朴酚和厚朴酚分别为162倍和338倍。此外，与和厚朴酚相比，在EC10-20时，8g在α1β2γ2和α1β1γ2亚型之间具有更大的分离窗口，因此提高了亚型选择性。
