Photoactive analogues of the haloether anesthetics provide high-resolution features from low-affinity interactions.
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.
Xi
Jin
J
Department of Anesthesiology & Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Liu
Renyu
R
Rossi
Matthew J
MJ
Yang
Jay
J
Loll
Patrick J
PJ
Dailey
William P
WP
Eckenhoff
Roderic G
RG
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
D000777:Anesthetics; D018685:Anesthetics, Inhalation; D019920:Photoaffinity Labels