Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A et al. TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluor ophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for α2- and α3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther 316: 410-422

Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 02/2006; 316(1):410-22. DOI: 10.1124/jpet.105.089920
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7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has partial agonist efficacy at the alpha2 and alpha3 subtypes and essentially antagonist efficacy at the alpha1 and alpha5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1-3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N-methyl-beta-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel alpha2/alpha3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

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    • "). The concentration range of each drug to be tested was carefully selected on the basis of their GABA A receptor subtype selectivity reported in the literature (Atack et al., 2006; Mirza et al., 2008; Munro et al., 2008; de Haas et al., 2009; Unekawa et al., 2012). A detailed summary on affinity and selectivity of each drug applied under study is summarized in Table 2. "
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    ABSTRACT: Cortical spreading depression (SD) is a transient propagating neuronal excitation followed by depression, which is generally accepted as the underlying cause of migraine. The inhibitory γ-aminobutyric acid type A (GABAA) receptor activation not only reduces cortical SD frequency and propagation, but also relieves migraine headache. This study aims to further determine the role of major subtypes of GABAA receptor in mediating SD genesis and propagation using an efficient in vitro chick retinal model. We firstly demonstrated that abundant α2, to a lesser extent, α5 of GABAA receptor expression in the chick retina, enabling the tissue useful for studying GABAA receptor pharmacology and SD. Marked suppression of SD by SL651498 and TPA023 were observed at 10 μmol·L(-1) and 50 μmol·L(-1) respectively, suggesting a critical role of GABAA receptor α subtypes, in particular α2, in modulating retinal SD elicitation and propagation. The negative data on NS11394 at 3 μmol·L(-1) and the little positive selectivity of TPA023 for α5 did not support that α5 subtype is involved in SD genesis and propagation. Our data provides strong evidence that α2, but not α5 is involved in early stage of migraine, indicating that α2 subtype a possible drug target related to migraine with aura. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Full-text · Article · Apr 2015 · Neuroscience
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    • "For the current studies, we compared the a2/a3/a5 subtypeselective PAM NS11394 [16], with the a2/a3 subtype-selective PAM TPA023 [17] [18], and the a3 subtype-selective PAM TP003 [19] on spinal wind-up. Aware that it can be difficult to assign absolute values to efficacy selectivity data obtained across labs due to the use of e.g. "
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    • "This Fig. 3. PET studies comparing TPA023B identify BZD binding sites in the human brain. (A) Comparison of the structures of TPA023B (Atack et al., 2011a), TPA023 (Atack et al., 2006b), and MRK-409 (Atack et al., 2011b). (B) Pseudocolor images on the left show the inhibition of [ 11 C]flumazenil binding produced by a single 1.5-mg oral dose of TPA023B in PET scans performed 1 hour before and 5 and 24 hours after dosing. "
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