Ro 15-4513: Partial inverse agonism at the BZR and interaction with ethanol☆
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Cited by (89)
Test-retest reproducibility of quantitative binding measures of [<sup>11</sup>C]Ro15-4513, a PET ligand for GABA<inf>A</inf>receptors containing alpha5 subunits
2017, NeuroImageCitation Excerpt :The synthesis of subtype-selective tracers such as Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate; F. Hoffmann–La Roche Ltd., Basel, Switzerland) promises further understanding of GABAA receptors. Ro15-4513 is an α5-subunit-selective imidazodiazepine that behaves as a partial inverse agonist at GABAA receptors (Bonetti et al., 1988; Lister and Nutt, 1988; Sadzot et al., 1989). Receptors that express α5 subunits have 10–15-fold higher affinity to Ro15-4513 than those that do not (Hadingham et al., 1993; Luddens et al., 1994).
Benzodiazepine modulation of homomeric GABA<inf>A</inf>ρ1 receptors: Differential effects of diazepam and 4′-chlorodiazepam
2014, European Journal of PharmacologyCitation Excerpt :These results indicate that BDZ modulation of responses mediated by GABAAρ1Rs is insensitive to flumazenil. The present findings demonstrate that the function of the human homomeric GABAAρRs can be effectively modulated by BDZs and that the sensitivity of GABAAρ1Rs to BDZs noticeably differs from that showed by other GABAARs subtypes (Bonetti et al., 1988; Harris et al., 1995; Möhler, 2011; Ramerstorfer et al., 2010; Sigel and Steinmann, 2012). The activity of GABAAρ1Rs expressed in oocytes was substantially potentiated by diazepam in the micromolar concentration range, whereas 4′-Cl diazepam, at equivalent concentrations, produced biphasic effects on current responses mediated by these receptors.
GABAergic transmission in hepatic encephalopathy
2013, Archives of Biochemistry and BiophysicsCitation Excerpt :Mechanisms of action of this substance at extrasynaptic δ-containing GABAAR are not yet precisely explored, but it was shown that Ro15-4513 possesses intrinsic activity, enhancing the cerebellar cGMP level in rats but not in mice, an effect antagonized by ethanol. Such activity is nearly absent in rat hippocampus, cortex or neostriatum [126]. Rescue of reduced cGMP levels in the cerebellum of hyperammonemic rats [47] would be expected for Ro15-4513.
The neurosteroid system: Implication in the pathophysiology of hepatic encephalopathy
2008, Neurochemistry InternationalDoes ethanol act preferentially via selected brain GABA<inf>A</inf> receptor subtypes? the current evidence is ambiguous
2007, AlcoholCitation Excerpt :Furthermore and more strikingly, a novel “ethanol binding site” on the GABAA receptor has been proposed, by indirect experiments showing that ethanol competitively displaces the imidazobenzodiazepine ligand Ro 15-4513 from its unconventional binding sites (Hanchar et al., 2006). Ro 15-4513 is the ligand that was in the 1980s regarded as a selective alcohol antagonist (Bonetti et al., 1985; Suzdak et al., 1986), in addition to its inverse agonist actions on certain GABAA receptor subtypes (Bonetti et al., 1988). So, do these interesting findings reveal the primary site of binding and mechanism of action of ethanol?
GABA<inf>A</inf> receptor subtypes: the "one glass of wine" receptors
2007, AlcoholCitation Excerpt :While we think that expression problems, in particular incorporation of δ subunits into functional receptors is the most likely reason for negative results, we cannot at this point exclude that there could be additional complexity, for example, due to accessory subunits and post-translational modifications like phosphorylation, present in some, but not all recombinant systems and cells, that might be required to reconstitute receptors from recombinant subunits that show functional properties (like high ethanol sensitivity) that resemble those of δ subunit-containing receptors that mediate alcohol-sensitive tonic currents in neurons. While classical BZs (like diazepam) and alcohol show a well-known synergism in their actions (Hu et al., 1987; Van Gorder et al., 1985), Hoffman La Roche scientists discovered in the early 1980s that a particular BZ called Ro15-4513 acts as a behavioral alcohol antagonist (Bonetti et al., 1988). This finding generated considerable excitement when subsequently verified in large numbers of studies and in many independent laboratories (Dar, 1992, 1995; Hellevuo and Korpi, 1988; Kolata, 1986; Lister and Nutt, 1987, 1988; Suzdak et al., 1986a; Syapin et al., 1987; Ticku and Kulkarni, 1988), but see Hellevuo and Korpi (1988).
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Abstracts of part of this work have been presented at the Eighth European Neuroscience Congress, the Hague, The Netherlands, September 11th–15th, 1984, at the Summer Meeting of the British Pharmacological Society, Southamptom, U.K., July 17th–19th, 1985, and at the 17th Annual Meeting of the Society for Neuroscience, New Orleans, LA, November 15th, 1987, at the Symposium “Antagonizing the behavioral effects of ethanol using drugs that act at the benzodiazepine/GABA receptor macromolecular complex.”