Discovery and Development of a Benzoquinone Molecule as a Novel Anesthetic

点击翻译按钮获取中文摘要

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.