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:  A Functionally Selective γ-Aminobutyric AcidA(GABAA) α2/α3-Subtype Selective Agonist That Exhibits Potent Anxiolytic Activity but Is Not Sedating in Animal Models

Carling, Robert W.; Madin, Andrew; Guiblin, Alec; Russell, Michael G. N.; Moore, Kevin W.; Mitchinson, Andrew; Sohal, Bindi; Pike, Andrew; Cook, Susan M.; Ragan, Ian; McKernan, Ruth M.; Quirk, Kathleen; Ferris, Pushpinder; Marshall, George R.; Thompson, Sally A.; Wafford, Keith A.; Dawson, Gerard R.; Atack, John; Harrison, Timothy; Castro, José L.; Street, Leslie J.

doi:10.1021/jm058034a

Cited by 51 publications

(33 citation statements)

References 30 publications

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“…TPA023 ( Fig. 1) was synthesized as described elsewhere (Carling et al, 2005 This precursor was reduced to the aldehyde and reacted with 3-chloro-4-(1,1-dimethyleth-1-yl)-6-hydrazinopyridazine to produce the imine N-[…”

Section: Methodsmentioning

confidence: 99%

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

Atack

Wafford²,

Tye³

et al. 2005

J Pharmacol Exp Ther

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175

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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 ␣1, ␣2, ␣3, or ␣5 subunit but has partial agonist efficacy at the ␣2 and ␣3 subtypes and essentially antagonist efficacy at the ␣1 and ␣5 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-␤-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel ␣2/␣3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.GABA A receptors are ligand-gated chloride ionophores that mediate the fast synaptic as well as tonic extrasynaptic inhibitory effects of GABA (Mody and Pearce, 2004). They are pentameric assemblies of proteins (Cromer et al., 2002) derived from a family of 16 genes (␣1-6, ␤1-3, ␥1-3, ␦, ⑀, , and ; Simon et al., 2004). Despite the theoretically large number of possible pentameric permutations that can arise from these 16 genes, only relatively few combinations are found within the central nervous system (McKernan and Whiting, 1996). Most of these native receptors contain ␣, ␤, and ␥ subunits in a 2:2:1 stoichiometry with an alternating ␣␤␣␤␥ arrangement as viewed from the synapse (Minier and Sigel, 2004).In addition to binding sites for their endogenous ligand, GABA A receptors also possess recognition sites for a number of pharmacologically active classes of compounds, including

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Section: Methodsmentioning

confidence: 99%

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

Atack

Wafford²,

Tye³

et al. 2005

J Pharmacol Exp Ther

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175

182

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“…Carling et al investigated that there is increasing evidence that compounds (45) with selectivity for gamma-aminobutyric acid-A (GABA-A) alpha2-and/ or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. In this study, they have described a novel series of GABA-A alpha2/alpha3 subtype-selective agonists leading to the identification of the non-sedating anxiolytic agents in preclinical animal assays [118]. …”

Section: Antianxiety Activitymentioning

confidence: 99%

Pharmacological significance of triazole scaffold

Kharb

Sharma

Yar

2010

Journal of Enzyme Inhibition and Medicinal Chemistry

483

236

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“…TPA023 (Atack et al, 2006) andTPA123 (TP13, McCabe et al, 2004;MRK-067, Atack, 2009) were synthesized as described by Carling et al (2005), where they were identified as compounds 17 and 15, respectively). For intravenous administration, they first were dissolved in polyethylene glycol 400, which then was diluted 50% with 0.9% sterile saline.…”

Section: Drugsmentioning

confidence: 99%

Reducing Abuse Liability of GABA_A/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α₁ and α_2/3 Subtypes

Ator¹,

Atack

Hargreaves³

et al. 2009

J Pharmacol Exp Ther

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Abuse-liability-related effects of subtype-selective GABA A modulators were explored relative to the prototypic benzodiazepine lorazepam. 7-Cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo [4,3-b]pyridazine (TPA123) has weak partial agonist efficacy at ␣ 1 -, ␣ 2 -, ␣ 3 -, and ␣ 5 -containing GABA A receptors, whereas 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) has weaker partial agonist efficacy at ␣ 2 and ␣ 3 and none at ␣ 1 and ␣ 5 subtypes. For both compounds, preclinical data suggested efficacy as nonsedating anxiolytics. Self-injection of TPA123 (0.0032-0.1 mg/kg) and TPA023 (0.0032-0.32 mg/ kg) was compared with lorazepam (0.01-0.32 mg/kg) in baboons. TPA123 and lorazepam maintained self-injection higher than vehicle at two or more doses in each baboon; peak rate of self-injection of lorazepam was higher than TPA123. Self-injected lorazepam and TPA123 also increased rates of concurrently occurring food-maintained behavior. After the availability of self-administered TPA123 doses ended, an effect consistent with a mild benzodiazepine-like withdrawal syndrome occurred. In contrast with lorazepam and TPA123, TPA023 did not maintain self-administration. Positron emission tomography studies showed that TPA023 produced a dose-dependent inhibition in the binding of [ 11 C]flumazenil to the benzodiazepine binding site in the baboon, which was essentially complete (i.e., 100% occupancy) at the highest TPA023 dose (0.32 mg/kg). In a physical dependence study, TPA023 (32 mg/kg/24 h) was delivered as a continuous intragastric drip. Neither flumazenil at 14 days nor stopping TPA023 after 30 to 31 days resulted in the marked withdrawal syndrome characteristic of benzodiazepines in baboons. In the context of other data, elimination of efficacy at the ␣ 1 subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced ␣ 2/3 subtype efficacy.When they were introduced in the early 1960s, the benzodiazepines, typified by diazepam, represented a major advance in the treatment of generalized anxiety disorder relative to older treatments (Lader, 1993). They had a rapid onset of anxiolytic efficacy, were generally well tolerated, and relatively safe in overdose. Nevertheless, beginning in the late 1970s, concerns over the abuse potential and dependence liability of benzodiazepines resulted in more restrictive legislation (i.e., legal scheduling under the Controlled Substances Act in the United States in 1975 and by the World Health Organization in 1982) as well as a general reluctance of physicians to prescribe benzodiazepines (Williams and McBride, 1998). Benzodiazepines are abused by people who have a history of drug abuse, those on long-term benzodiazepines may independently escalate their dosage, patients can be overly reluctant to comply with physician recommendations to reduce benzodiazepine use, and there is considerable evidence of adverse ...

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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: A Functionally Selective γ-Aminobutyric Acid_A(GABA_A) α2/α3-Subtype Selective Agonist That Exhibits Potent Anxiolytic Activity but Is Not Sedating in Animal Models

Cited by 51 publications

References 30 publications

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

Pharmacological significance of triazole scaffold

Reducing Abuse Liability of GABA_A/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α₁ and α_2/3 Subtypes

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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: A Functionally Selective γ-Aminobutyric AcidA(GABAA) α2/α3-Subtype Selective Agonist That Exhibits Potent Anxiolytic Activity but Is Not Sedating in Animal Models

Cited by 51 publications

References 30 publications

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABAAReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABAAReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

Pharmacological significance of triazole scaffold

Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α1 and α2/3 Subtypes

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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: A Functionally Selective γ-Aminobutyric Acid_A(GABA_A) α2/α3-Subtype Selective Agonist That Exhibits Potent Anxiolytic Activity but Is Not Sedating in Animal Models

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

TPA023 [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], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

Reducing Abuse Liability of GABA_A/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α₁ and α_2/3 Subtypes