Hall Belinda J, Karim Nasiara, Chebib Mary, Johnston Graham A R, Hanrahan Jane R
Department of Pharmacology, The University of Sydney, Sydney, NSW, 2006, Australia.
Neurochem Res. 2014 Jun;39(6):1068-78. doi: 10.1007/s11064-013-1157-2. Epub 2013 Sep 29.
We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2β2γ2L GABAA and ρ1 GABAC receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABAC receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABAA receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABAA receptors. 6-Methoxyflavanone inhibited [(3)H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABAA receptors and it's partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.
我们使用双电极电压钳和放射性配体结合技术，评估了6-甲氧基黄烷酮和6-甲氧基黄酮对野生型α1/α2β2γ2L GABAA受体和ρ1 GABAC受体，以及对非洲爪蟾卵母细胞中表达的突变型ρ1I307S、ρ1W328M、ρ1I307S/W328M GABAC受体的影响。6-甲氧基黄烷酮和6-甲氧基黄酮可作为氟马西尼不敏感的正变构调节剂，作用于人重组α1β2γ2L和α2β2γ2L GABAA受体的GABA反应。然而，与6-甲氧基黄酮不同，6-甲氧基黄烷酮在α1β2 GABAA受体上相对无活性。6-甲氧基黄烷酮抑制[(3)H]-氟硝西泮与大鼠脑膜的结合。发现这两种黄酮类化合物作为调节剂在ρ1、ρ1I307S和ρ1W328M GABA受体上无活性，但在苯二氮䓬敏感的ρ1I307S/W328M GABA受体上作为GABA的正变构调节剂起作用。这种双突变体保留了ρ1对荷包牡丹碱不敏感且被TPMPA和THIP拮抗的特性。此外，6-甲氧基黄烷酮在ρ1W328M GABA受体上也是部分激动剂。6-甲氧基黄烷酮在α1β2 GABAA受体上的相对无活性及其在ρ1W328M GABA受体上的部分激动剂作用表明，它具有其他黄酮类化合物所不具备的独特特性。
