title: Photoaffinity ligands for the [3H]TBOB binding site of the GABAA receptor.
abstract: Two types of 1-substituted-4-t-butyl-2,6,7-trioxabicyclo[2.2.2]octanes are examined as candidate photoaffinity ligands to irreversibly inhibit the [3H]TBOB binding site of the GABAA receptor complex present in bovine brain membranes. The 1-substituted-(4-bromo-6-diazocyclohexa -1,4-dien-3-onyl) derivative (IC50 1.1 microM) dissociates completely in the dark, but on irradiation produces over 40% photoirreversible inhibition of [3H]TBOB binding. This photoinactivation can be partially (64%) protected using a potent and completely dissociating TBOB analog. The 1-substituted-(4-azidophenyl) derivative (IC50 149 nM) also dissociates completely in the dark and at 2.2 microM gives 20% photoirreversible inhibition which is completely protectable. The corresponding 1-(4-azido-3,5-dichlorophenyl) analog and its 4-(1-methylpropyl) isomer are 16- and 8-fold more potent inhibitors, respectively, than the azidophenyl derivative but these dichloro probes are not examined further because they do not dissociate in the dark by an apparently non-covalent mechanism. Thus, the bromodiazocyclohexadienonyl and azidophenyl compounds photoirreversibly and therefore covalently modify the [3H]TBOB binding site of the GABAA receptor complex.
authors.affiliation: Department of Entomological Sciences, University of California, Berkeley 94720.
authors.forename: J E
authors.initials: JE
authors.lastname: Hawkinson
authors.forename: M P
authors.initials: MP
authors.lastname: Goeldner
authors.forename: C J
authors.initials: CJ
authors.lastname: Palmer
authors.forename: J E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000345:Affinity Labels / Q000378:metabolism*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002417:Cattle; D066298:In Vitro Techniques; D008024:Ligands; D015394:Molecular Structure; D010777:Photochemistry; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D000345:Affinity Labels; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D011963:Receptors, GABA-A; C070433:1-(4-cyanophenyl)-4-(1-methylprop-2-enyl)-2,6,7-trioxabicyclo(2.2.2)octane; C070435:4-t-butyl-1-phenyl-2,6,7-trioxabicyclo(2.2.2)octane; C070434:1-(4-azidophenyl)-4-t-butyl-2,6,7-trioxabicyclo(2.2.2)octane