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
ABSTRACT 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. "
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.Neuroscience 04/2015; 298. DOI:10.1016/j.neuroscience.2015.04.016 · 3.36 Impact Factor
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- "For the current studies, we compared the a2/a3/a5 subtypeselective PAM NS11394 , with the a2/a3 subtype-selective PAM TPA023  , and the a3 subtype-selective PAM TP003  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. "
ABSTRACT: GABAA receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain. Restoration of diminished spinal GABAA-α2 and -α3 subunit-containing receptor function is a principal contributor to this analgesia, albeit involvement of GABAA-α5-receptors has not been excluded. Thus, we compared NS11394 and TPA023 (PAMs with selectivity/efficacy at GABAA-α2/α3/α5 receptors) with TP003 (a reportedly GABAA-α3 selective PAM) against spinal sensitization. However, in-house electrophysiology studies designed to confirm the selectivity of TPA023 and TP003 for human GABAA receptors did not corroborate published data, with TP003 displaying considerable GABAA-α5 receptor efficacy. Therefore, we identified a novel PAM, NS16085, which possesses negligible efficacy at GABAA-α5 receptors, but with GABAA-α2/α3 efficacy equivalent to NS11394. At the GABAA-α1 receptor the compound gives low level of negative modulation further separating it from the other compounds. Rat pups with carrageenan-induced hindpaw inflammatory hyperalgesia were used to make ex-vivo spinal dorsal root-evoked ventral root recordings. Some spontaneous activity and large numbers of spikes to repetitive stimulation of dorsal roots at C-fibre intensity, indicative of wind-up and sensitization were observed. Equimolar concentrations of NS11394, TP003 and NS16085 all attenuated wind-up to a similar degree; TPA023 was clearly less effective. In adult rats, NS16085 (3-30 mg/kg, p.o.) dose-dependently reduced formalin-induced hindpaw flinching with efficacy comparable to NS11394. Thus, potentiation of GABAA-α2 and-α3 receptors is sufficient to depress spinal sensitization and mediate analgesia after inflammatory injury. Positive modulation at GABAA-α5-receptors is apparently dispensable for this process, an important consideration given the role of this receptor subtype in cognitive function.Biochemical Pharmacology 12/2014; 93(3). DOI:10.1016/j.bcp.2014.12.010 · 5.01 Impact Factor
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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. "
ABSTRACT: Anxiety disorders are a major public health concern. Here, we examine the familiar area of anxiolysis in the context of a systems-level understanding that will hopefully lead to revealing an underlying pharmacological connectome. The introduction of benzodiazepines nearly half a century ago markedly improved the treatment of anxiety disorders. These agents reduce anxiety rapidly by allosterically enhancing the postsynaptic actions of GABA at inhibitory type A GABA receptors but side effects limit their use in chronic anxiety disorders. Selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors have emerged as an effective first-line alternative treatment of such anxiety disorders. However, many individuals are not responsive and side effects can be limiting. Research into a relatively new class of agents known as neurosteroids has revealed novel modulatory sites and mechanisms of action that are providing insights into the pathophysiology of certain anxiety disorders, potentially bridging the gap between the GABAergic and serotonergic circuits underlying anxiety. However, translating the pharmacological activity of compounds targeted to specific receptor subtypes in rodent models of anxiety to effective therapeutics in human anxiety has not been entirely successful. Since modulating any one of several broad classes of receptor targets can produce anxiolysis, we posit that a systems-level discovery platform combined with an individualized medicine approach based on noninvasive brain imaging would substantially advance the development of more effective therapeutics.Pharmacological Reviews 10/2014; 66(4):1002-1032. DOI:10.1124/pr.114.009126 · 17.10 Impact Factor