11-trifluoromethyl-phenyldiazirinyl neurosteroid analogues: potent general anesthetics and photolabeling reagents for GABAA receptors.
11-trifluoromethyl-phenyldiazirinyl neurosteroid analogues: potent general anesthetics and photolabeling reagents for GABAA receptors.
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11-三氟甲基 - 苯基二氮嗪类神经类似类似物：GABAA受体的有效的一般麻醉和光标记试剂。
DOI：
10.1007/s00213-014-3568-4
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发表时间：
2014-09
影响因子：
3.4
通讯作者：
Evers, Alex S.
中科院分区：
文献类型：
--
作者：
Chen, Zi-Wei;Wang, Cunde;Krishnan, Kathiresan;Manion, Brad D.;Hastings, Randy;Bracamontes, John;Taylor, Amanda;Eaton, Megan M.;Zorumski, Charles F.;Steinbach, Joseph H.;Akk, Gustav;Mennerick, Steven;Covey, Douglas F.;Evers, Alex S.
虽然神经类固醇是GABAA受体的正变构调节剂，但介导这些作用的结合部位尚未确定。合成神经类固醇类似物光标记试剂，该试剂可模拟内源性神经类固醇的生物学效应，并具有光化学性质，可用作鉴定神经类固醇与GABAA受体结合部位的工具。合成了两个含有三氟甲基苯基二氮杂环连接到甾体C11位的神经甾体类似物。这些试剂CW12和CW14分别是别孕酮(5α还原类固醇)和孕酮(5β还原类固醇)的类似物。这两种试剂都具有良好的光化学性质，可以有效地插入环己烷的C-H键。它们还有效地复制了别孕酮和孕烯醇酮对GABAA受体功能的作用：它们增强了转导α1β2γ2L亚基的非洲爪哇卵母细胞的GABA诱导电流，调节了大鼠脑膜上的[35S]双环硫代磷酸叔丁基酯结合，是非洲爪哇蝌蚪的有效麻醉剂。用[~H]CW_(12)和[~H]CW_(14)进行的研究表明，这些试剂在大鼠脑膜和在表达α_1和β_2亚基或β_3亚基的TSA细胞中共价标记GABA_A受体。大鼠脑内GABAA受体的光标记既具有浓度依赖性，又具有立体特异性。CW12和CW14具有合适的光化学和药理学特性，可用作光标记试剂来识别GABAA受体上的特定神经类固醇结合部位。
While neurosteroids are well-described positive allosteric modulators of GABAA receptors, the binding sites that mediate these actions have not been definitively identified. To synthesize neurosteroid analogue photolabeling reagents that closely mimic the biological effects of endogenous neurosteroids and have photochemical properties that will facilitate their use as tools for identifying the binding sites for neurosteroids on GABAA receptors. Two neurosteroid analogues containing a trifluromethyl-phenyldiazirine group linked to the steroid C11 position were synthesized. These reagents, CW12 and CW14, are analogues of allopregnanolone (5α-reduced steroid) and pregnanolone (5β-reduced steroid), respectively. Both reagents were shown to have favorable photochemical properties with efficient insertion into the C–H bonds of cyclohexane. They also effectively replicated the actions of allopregnanolone and pregnanolone on GABAA receptor functions: they potentiated GABA-induced currents in Xenopus laevis oocytes transfected with α1β2γ2L subunits, modulated [35S]t-butylbicyclophosphorothionate binding in rat brain membranes and were effective anesthetics in Xenopus tadpoles. Studies using [3H]CW12 and [3H]CW14 showed that these reagents covalently label GABAA receptors in both rat brain membranes and in TSA cells expressing either α1 and β2 subunits or β3 subunits of the GABAA receptor. Photolabeling of rat brain GABAA receptors was shown to be both concentration-dependent and stereospecific. CW12 and CW14 have the appropriate photochemical and pharmacological properties for use as photolabeling reagents to identify specific neurosteroid binding sites on GABAA receptors.
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DOI：
10.1124/jpet.109.164079
发表时间：
2010-05-01
影响因子：
3.5
作者：
Evers, Alex S.;Chen, Zi-Wei;Covey, Douglas F.
通讯作者：
Covey, Douglas F.
影响因子：
4.7
作者：
BUREAU, MH;OLSEN, RW
通讯作者：
OLSEN, RW
影响因子：
4.4
作者：
Srinivasan, S;Sapp, DW;Olsen, RW
通讯作者：
Olsen, RW
影响因子：
5.3
作者：
Akk G;Covey DF;Evers AS;Mennerick S;Zorumski CF;Steinbach JH
通讯作者：
Steinbach JH
影响因子：
3.6
作者：
Chen, Zi-Wei;Manion, Brad;Evers, Alex S.
通讯作者：
Evers, Alex S.