Discovery and Development of a Benzoquinone Molecule as a Novel Anesthetic

尽管该领域在理解麻醉剂如何引起无意识方面取得了实质性进展， 健忘症和固定，确切的机制仍然知之甚少。另外，所有的镇静剂- 催眠剂引起不希望副作用。因此，有必要发现新的镇静催眠药 并增进我们对其作用机制的了解。我们之前发现麻醉剂， 异丙酚，干扰线粒体内辅酶Q（CoQ）水平的电子传递，并诱导 过量质子泄漏这些“两次打击”结合在一起，损害了线粒体膜电位（Δ μ m） 通过降低质子原动力并防止电子通量的必要斜坡上升来再生它。 初步工作中，我们观察到合成辅酶Q类似物（1，4-苯醌类成员）引起 线粒体渗漏也有类似增加，并促使Δ m下降。通过这些观察，我们 发现尾静脉注射短链辅酶Q类似物，泛醌-5（Ub 5）， 小鼠的无意识这些挑衅性的发现使我们得出了我们的全球假设：1，4-苯醌 代表了一种新型的镇静催眠药我们特别假设Ub 5导致无意识 通过牺牲Δ Δ m。因此，目的旨在：1）表征Ub 5的麻醉作用和2） 确定Ub 5如何阻止前脑线粒体产生足够的Δ Δ μ m。第三个目标是 旨在确定神经元谷氨酸-谷氨酸线粒体载体Arrhythmia，作为一种新的 麻醉相关靶点。这一目标的基础是我们的初步数据，这些数据表明， Arrhythmia是Ub 5介导的质子泄漏的主要来源。在具体目标#3中，我们将确定Arrhythmia的作用， 介导Ub 5引起的无意识。该提案的成功将使Ub 5成为一种新型麻醉剂 代理和阐明离散线粒体的作用机制。获得的知识将使我们能够发现 在未来的工作中，镇静催眠药具有精确的线粒体靶点;最大限度地提高靶向治疗 生物活性和最小化脱靶毒性作用。

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.