title: Photoactive analogues of the haloether anesthetics provide high-resolution features from low-affinity interactions.
abstract: The difficulty in obtaining binding target and site information for low-affinity drugs, like the inhaled anesthetics, has limited identification of their molecular effectors. Because such information can be provided by photoactive analogues, we designed, synthesized, and characterized a novel diazirnyl haloether that closely mimics isoflurane, the most widely used clinical general anesthetic. This compound, H-diaziflurane, is a nontoxic, potent anesthetic that potentiates GABA-gated ion channels in primary cultures of hippocampal neurons. Calorimetric and structural characterizations show that H-diaziflurane binds a model anesthetic host protein with similar energetics as isoflurane and forms photoadducts with residues lining the isoflurane binding site. H-diaziflurane will be immediately useful for identifying targets and sites important for the molecular pharmacology of the inhaled haloether anesthetics.
authors.affiliation: Department of Anesthesiology & Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Xi
authors.forename: Renyu
authors.initials: R
authors.lastname: Liu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Rossi
authors.forename: Jay
authors.initials: J
authors.lastname: Yang
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Loll
authors.forename: William P
authors.initials: WP
authors.lastname: Dailey
authors.forename: Roderic G
authors.initials: RG
authors.lastname: Eckenhoff
mesh_terms: D000777:Anesthetics / Q000737:chemistry / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002151:Calorimetry; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019920:Photoaffinity Labels / Q000737:chemistry* / Q000378:metabolism*; D014981:Xenopus
chemical_list: D000777:Anesthetics; D018685:Anesthetics, Inhalation; D019920:Photoaffinity Labels