title: [4-Dimethyl-3-t-butylcarboxyl-4,5-dihydro (1,5-a) quinoxaline] is a novel ligand to the picrotoxin site on GABAA receptors, and decreases single-channel open probability.
abstract: U-93631,[4-dimethyl-3-t-butylcarboxyl-4,5-dihydro (1,5-a) quinoxaline], represents a GABAA receptor ligand of novel chemical structure, and has been shown to induce a rapid, time-dependent decay of GABA-induced whole-cell Cl- currents in recombinant GABAA receptors (Dillon et al., 1993). In this study, we found that the drug competitively inhibited [35S]t-butylbicyclophosphorothionate binding to the picrotoxin site on a cloned GABAA receptor, alpha 1 beta 2 gamma 2, and preempted the action of picrotoxin and [35S]t-butylbicyclophosphorothionate on GABA-induced Cl- currents. We further examined the effect of U-93631 on GABA-induced single channel openings in outside-out patches. U-93631 (5 microM) showed no effect on single channel conductance, the duration of channel open states or the short closed state, but increased the duration of the long closed state and its relative contribution to total closed time. In addition, closings of very long duration (> 500 msec), albeit rare, occurred more frequently in the presence of U-93631. Thus, the probability of single channel openings decreased from 0.12 +/- 0.02 to 0.04 +/- 0.01 in the presence of U-93631 (5 microM). These properties of U-93631 are analogous to those of picrotoxin and [35S]t-butylbicyclophosphorothionate reported in earlier studies with native neurons. We conclude that U-93631 at least shares overlapping binding domains with picrotoxin and [35S]t-butylbicyclophosphorothionate, and the ability to stabilize the GABAA receptor/Cl- channel complex in an inactivated state(s).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: CNS Diseases Research, Upjohn Company, Kalamazoo, Michigan.
authors.forename: G H
authors.initials: GH
authors.lastname: Dillon
authors.forename: W B
authors.initials: WB
authors.lastname: Im
authors.forename: J F
authors.initials: JF
authors.lastname: Pregenzer
authors.forename: D B
authors.initials: DB
authors.lastname: Carter
authors.forename: B J
authors.initials: BJ
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D008024:Ligands; D010852:Picrotoxin / Q000378:metabolism*; D011810:Quinoxalines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007473:Ion Channels; D008024:Ligands; D010852:Picrotoxin; D011810:Quinoxalines; D011963:Receptors, GABA-A; D015032:Zinc; C083857:U 93631; C037476:tert-butylbicyclophosphorothionate