Hall Belinda J, Chebib Mary, Hanrahan Jane R, Johnston Graham A R
Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia.
Eur J Pharmacol. 2005 Apr 11;512(2-3):97-104. doi: 10.1016/j.ejphar.2005.02.034.
6-Methylflavanone acted as a positive allosteric modulator of gamma-aminobutyric acid (GABA) responses at human recombinant alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus laevis oocytes. It was essentially inactive at rho1 GABA(C) receptors. The EC50 values for 6-methylflavanone for the positive modulation of the EC(10-20) GABA responses were 22 microM, 10 microM and 6 microM and the maximum potentiations were 120%, 417% and 130% at alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via alpha2-containing GABA(A) receptors, while sedation is thought to be mediated via alpha1-containing GABA(A) receptors. We have previously reported that 6-methylflavone (1-100 microM) produced positive allosteric modulation at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors with no significant difference between the enhancement seen at either receptor subtype. In the present study, 6-methylflavone was tested at alpha2beta2gamma2L GABA(A) receptors and found to maximally potentiate the EC(10-20) GABA response by 183+/-39% which is similar to that previously observed for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors. Thus, 6-methylflavone did not show a preference for alpha2beta2gamma2L over alpha1beta2gamma2L GABA(A) receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at alpha2beta2gamma2L GABA(A) receptors, and less efficacious at alpha1beta2gamma2L GABA(A) receptors. This may represent a relatively unique type of selectivity for positive modulators of GABA-A receptor subtypes based on efficacy as distinct from potency. As was previously shown for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors, the positive modulation of GABA responses at alpha1beta2gamma2L and alpha2beta2gamma2L GABA(A) receptors by 6-methylflavanone was insensitive to antagonism by flumazenil, indicating that this action is not mediated via "high-affinity" benzodiazepine sites.
6-甲基黄酮在非洲爪蟾卵母细胞中表达的人重组α1β2γ2L、α2β2γ2L和α1β2 GABA(A)受体上，作为γ-氨基丁酸（GABA）反应的正变构调节剂发挥作用。它在rho1 GABA(C)受体上基本无活性。6-甲基黄酮对EC(10 - 20) GABA反应进行正调节的EC50值分别为22 microM、10 microM和6 microM，在α1β2γ2L、α2β2γ2L和α1β2 GABA(A)受体上的最大增强倍数分别为120%、417%和130%。因此，6-甲基黄酮作为α2β2γ2L受体的正调节剂比作为α1β2γ2L和α1β2 GABA(A)受体的正调节剂更有效。这可能具有重要意义，因为地西泮诱导的抗焦虑作用被认为是通过含α2的GABA(A)受体介导的，而镇静作用被认为是通过含α1的GABA(A)受体介导的。我们之前报道过，6-甲基黄酮（1 - 100 microM）在α1β2γ2L和α1β2 GABA(A)受体上产生正变构调节作用，在这两种受体亚型上观察到的增强作用之间没有显著差异。在本研究中，对6-甲基黄酮在α2β2γ2L GABA(A)受体上进行了测试，发现其最大可使EC(10 - 20) GABA反应增强183±39%，这与之前在α1β2γ2L GABA(A)受体上观察到的6-甲基黄酮的增强作用相似。因此，就效力而言，6-甲基黄酮在α2β2γ2L和α1β2γ2L GABA(A)受体之间没有表现出对α2β2γ2L的偏好。与6-甲基黄酮相比，6-甲基黄酮作为α2β2γ2L GABA(A)受体的正变构调节剂更有效力，而作为α1β2γ2L GABA(A)受体的正变构调节剂效力较低。这可能代表了一种基于效力而非亲和力的相对独特的GABA-A受体亚型正调节剂选择性类型。正如之前在α1β2γ2L GABA(A)受体上对6-甲基黄酮所显示的那样，6-甲基黄酮对α1β2γ2L和α2β2γ2L GABA(A)受体的GABA反应的正调节作用对氟马西尼的拮抗作用不敏感，这表明该作用不是通过“高亲和力”苯二氮䓬位点介导的。
