Discovery and Development of a Benzoquinone Molecule as a Novel Anesthetic

尽管该领域在了解麻醉剂如何导致昏迷方面取得了实质性进展， 失忆症和制动，确切的机制仍然知之甚少。此外，所有的镇静剂- 催眠剂会产生不良的副作用。因此，有必要发现新的镇静催眠药。 并促进我们对他们(S)的作用机制的了解。我们之前发现麻醉剂， 异丙酚在辅酶Q(CoQ)水平上干扰线粒体内电子传递并诱导 质子泄漏过多。这些“两击”结合在一起，损害了线粒体膜电位(ΔΨm)。 通过降低质子动力并阻止必要的电子通量上升来再生它。在……里面 在前期工作中，我们观察到合成辅酶Q类似物(1，4-苯醌类成员)会引起 类似的线粒体泄漏增加并导致ΔΨm下降。扩展这些观察，我们 发现尾静脉注射短链辅酶Q类似物泛醌-5(Ub5)立即诱导 小鼠的无意识。这些具有挑衅性的发现引出了我们的全球假说：1，4-苯二酚 代表了一种新型的镇静催眠药。我们特别假设Ub5会导致无意识 因此，目的是为了：1)表征ΔΨ和2)的麻醉效果 确定Ub5如何阻止前脑线粒体产生足够的ΔΨm。第三个目标是 旨在将神经元天冬氨酸-谷氨酸线粒体载体Aralar鉴定为一种新的 药理上相关的麻醉剂靶标。这一目标的基础是我们的初步数据表明 Aralar是Ub5介导的质子泄漏的主要来源。在具体目标3中，我们将确定Aralar在 介导Ub5诱导的无意识状态。该提案的成功将使Ub5成为一种新的麻醉剂 并阐明离散的线粒体作用机制。获得的知识将使我们能够发现 镇静剂-未来工作中具有精确线粒体靶点的催眠药；最大限度地实现靶向治疗 生物活性和最大限度地减少偏离目标的毒性影响。

Although the field has made substantial progress in understanding how anesthetics induce unconsciousness, amnesia, and immobilization, the exact mechanisms remain poorly understood. Furthermore, all sedative- hypnotic agents cause undesirable adverse effects. Thus, there is a need to discover new sedative-hypnotics and to advance our knowledge of their mechanism(s) of action. We previously found that the anesthetic, propofol, interfered with electron transfer within mitochondria at the level of coenzyme Q (CoQ) and induced excessive proton leak. These “two-hits” combined to compromise the mitochondrial membrane potential (ΔΨm) by degrading the proton motive force and preventing the requisite ramp up in electron flux to regenerate it. In preliminary work, we observed that synthetic CoQ analogs (members of the 1,4-benzoquinone class) cause a similar increase in mitochondrial leak and precipitate a decline in ΔΨm. Extending these observations, we found that tail vein injection of the short-chain CoQ analog, ubiquinone-5 (Ub5), immediately induced unconsciousness in mice. These provocative findings led us to our global hypothesis: 1,4-benzoquinones represent a novel class of sedative-hypnotics. We specifically hypothesize that Ub5 induces unconsciousness by compromising ΔΨm. Thus, the aims are designed to: 1) characterize the anesthetic effects of Ub5 and 2) determine how Ub5 prevents forebrain mitochondria from generating an adequate ΔΨm. The third aim is designed to identify the neuronal aspartate-glutamate mitochondrial carrier, Aralar, as a novel pharmacologically relevant anesthetic target. The basis for this aim is our preliminary data demonstrating that Aralar is a major source of Ub5-mediated proton leak. In specific aim #3 we will determine the role of Aralar in mediating Ub5-induced unconsciousness. Success of the proposal will establish Ub5 as a novel anesthetic agent and elucidate discrete mitochondrial mechanisms of action. Knowledge gained will permit us to discover sedative-hypnotics with precise mitochondrial targets in future work; maximizing on-target therapeutic biological activity and minimizing off-target toxic effects.