title: Halogenated diazirines as photolabel mimics of the inhaled haloalkane anesthetics.
abstract: The inhaled anesthetics are low affinity volatile compounds whose mechanism of action remains unclear, in part due to the difficulty of determining their binding targets. Photolabeling may help resolve this difficulty, and thus we have synthesized six compounds (four previously unreported) with structural and physical similarity to halothane (1-bromo-1-chloro-2,2,2-trifluoroethane), a commonly used clinical anesthetic. These compounds incorporate either a diazo, diazirine, or azido group to provide photolability in the long-UV range and to provide a highly reactive photolysis product. While several of the compounds have immobilizing activity in tadpoles, it is complicated by either toxicity or very low potency. One compound however, a halogenated three-carbon diazirine 4, is a potent anesthetic, is apparently nontoxic, potentiates GABA(A) Cl(-) currents, and stabilizes serum albumin, all of which are features of halothane. When tagged with radioactivity, this compound should serve as a reasonable probe of haloalkane anesthetic binding targets and sites.
authors.affiliation: Department of Anesthesia, University of Pennsylvania Health System, 3400 Spruce Street, Philadelphia, Pennsylvania 19104-4283, USA. roderic.eckenhoff@uphs.upenn.edu
authors.forename: Roderic G
authors.initials: RG
authors.lastname: Eckenhoff
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Knoll
authors.forename: Eric P
authors.initials: EP
authors.lastname: Greenblatt
authors.forename: William P
authors.initials: WP
authors.lastname: Dailey
mesh_terms: D018685:Anesthetics, Inhalation / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006221:Halothane / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006859:Hydrogen; D066298:In Vitro Techniques; D007814:Larva; D018716:Molecular Mimicry; D015394:Molecular Structure; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010777:Photochemistry; D017510:Protein Folding; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D012709:Serum Albumin / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D014316:Tritium; D014981:Xenopus
chemical_list: D018685:Anesthetics, Inhalation; D018118:Chloride Channels; D019920:Photoaffinity Labels; D011963:Receptors, GABA-A; D012709:Serum Albumin; D014316:Tritium; D003978:Diazomethane; D006859:Hydrogen; D006221:Halothane