Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics
type: CreativeWork
description: General anesthetics have played a pivotal role in the history of medicine. Despite accounts of their use within the earliest of human records, our understanding of anesthetic mechanisms remains unclear. Understanding these molecular mechanisms would be a significant advance toward enhanced drug design and optimal the clinical use of these potentially hazardous agents. Recent advances in chemical and molecular biology, including photoaffinity labeling, have allowed enhanced appreciation of the complex interactions anesthetic’s have with their macromolecular substrates. This work is dedicated to further define the protein interactions of the frequently administered volatile anesthetics sevoflurane and isoflurane, as well as the most commonly used intravenous anesthetic, propofol. A novel photoaffinity ligand for sevoflurane was validated and applied to uncover the unique mechanism of sevoflurane positive modulation of mammalian Shaker Kv1.2 channels. This novel sevoflurane photoaffinity ligand was in addition to a previously developed photoaffinity ligand for isoflurane, further applied to determine the anesthetic binding sites within a vital protein target, synaptic GABAA receptors. The molecular recognition elements for propofol-protein interactions were probed using a novel hydrogen-bond null derivative. It was determined that the propofol 1-hydroxyl is key for molecular interactions that contribute to anesthetic endpoints, such as synaptic GABAA receptor positive modulation, while less significant for other known biological effects like decreasing muscle contractility. The range of propofol-binding proteins within synaptosomes was further defined with the synthesis of a novel photoaffinity tandem click chemistry-active ligand and the development of a quantitative affinity-based protein profiling workflow. Results of the investigation indicated a highly complex pool of propofol-specific proteins including an unbiased, selective binding of specific synaptic GABAA re…
abstract: General anesthetics have played a pivotal role in the history of medicine. Despite accounts of their use within the earliest of human records, our understanding of anesthetic mechanisms remains unclear. Understanding these molecular mechanisms would be a significant advance toward enhanced drug design and optimal the clinical use of these potentially hazardous agents. Recent advances in chemical and molecular biology, including photoaffinity labeling, have allowed enhanced appreciation of the complex interactions anesthetic’s have with their macromolecular substrates. This work is dedicated to further define the protein interactions of the frequently administered volatile anesthetics sevoflurane and isoflurane, as well as the most commonly used intravenous anesthetic, propofol. A novel photoaffinity ligand for sevoflurane was validated and applied to uncover the unique mechanism of sevoflurane positive modulation of mammalian Shaker Kv1.2 channels. This novel sevoflurane photoaffinity ligand was in addition to a previously developed photoaffinity ligand for isoflurane, further applied to determine the anesthetic binding sites within a vital protein target, synaptic GABAA receptors. The molecular recognition elements for propofol-protein interactions were probed using a novel hydrogen-bond null derivative. It was determined that the propofol 1-hydroxyl is key for molecular interactions that contribute to anesthetic endpoints, such as synaptic GABAA receptor positive modulation, while less significant for other known biological effects like decreasing muscle contractility. The range of propofol-binding proteins within synaptosomes was further defined with the synthesis of a novel photoaffinity tandem click chemistry-active ligand and the development of a quantitative affinity-based protein profiling workflow. Results of the investigation indicated a highly complex pool of propofol-specific proteins including an unbiased, selective binding of specific synaptic GABAA re…
author: Woll, Kellie Ann
language: en
date published: 2017
date modified: 2026-07-24T03:45:38Z
provider: University of Pennsylvania
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Pennsylvania