Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates.
Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates.
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发表时间：
1989-03
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通讯作者：
D. Turner;R. Ransom;J. Yang;R. Olsen
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作者：
D. Turner;R. Ransom;J. Yang;R. Olsen
比较了类固醇麻醉剂α-黄体酮和一系列天然类似物以及催眠剂巴比妥酸戊巴比妥与γ-氨基丁酸(GABA)受体的相互作用：大鼠脑膜上的结合部位和用大鼠海马片测量的~(36)Cl-通量的功能活性。类固醇增强了[~3H]蝇咪酚与GABA受体的结合，增强了[~3H]氟硝西潘与苯二氮卓受体的结合，抑制了[35S]-叔丁基双环磷硫酸盐与GABA受体-氯通道复合体上的印防己毒素/惊厥结合部位的结合。同样的类固醇在微摩尔浓度下调节配体与GABA受体复合体上不同受体位置的结合，增加了蝇草醇刺激的大鼠海马片的~(36)Cl-通量。类固醇和巴比妥酸盐一样，增加了对蝇草酚的最大反应，但在没有GABA激动剂的情况下，很少或根本没有增强基础的~(36)Cl-通量。尽管类固醇和巴比妥酸盐的作用相似，但两类化合物结合在一起时，以及在没有GABA激动剂的情况下对~(36)Cl-通量具有相加或协同作用的观察，最终证明了不同的作用部位。构效关系研究表明，合成类固醇麻醉剂α-黄酮类化合物活性最强，其次是天然类固醇类化合物四氢脱氧皮质酮、别氢四氢皮质酮、顺式雄酮和5α-雄烷-17β-醇-3-酮。几种自然产生的类固醇能够增强大脑中GABA介导的抑制作用，这表明可能存在神经功能的内源性类固醇调节剂。
The steroid anesthetic alphaxalone and a series of naturally occurring analogs were compared in potency and efficacy with each other and the hypnotic barbiturate pentobarbital for interaction with gamma-aminobutyric acid (GABA) receptors:binding sites in rat brain membranes and functional activity in 36Cl- flux measurements with rat hippocampal slices. The steroids enhanced [3H]muscimol binding to GABA receptor sites, enhanced [3H] flunitrazepam binding to benzodiazepine receptors and inhibited [35S]t-butyl bicyclophosphorothionate binding to picrotoxin/convulsant binding sites on the GABA receptor-chloride channel complex. The same steroids that were active in modulating the binding of ligands to the various receptor sites on the GABA receptor complex at micromolar concentrations enhanced muscimol-stimulated 36Cl- flux in rat hippocampal slices. The steroids, like the barbiturates, increased the maximal response to muscimol but produced little or no potentiation of basal 36Cl- flux in the absence of GABA agonist. Although the effects of steroids and barbiturates were similar, separate sites of action were demonstrated conclusively by the observation that the two classes of compounds, when included together, gave additive or synergistic effects on binding, as well as on 36Cl- flux in the absence of GABA agonist. Structure-activity studies showed that the synthetic steroid anesthetic alphaxalone was the most potent compound tested, followed by the naturally occurring steroids tetrahydro-deoxycorticosterone, allo-tetrahydrocorticosterone, cis-androsterone and 5 alpha-androstan-17 beta-ol-3-one. The ability of several naturally occurring steroids to enhance GABA-mediated inhibition in the brain suggests the possibility of an endogenous steroid modulator of neuronal function.