Tpa023 [7-(1,1-Dimethylethyl)-6-(2-Ethyl-2h-1,2,4-Triazol-3-Ylmethoxy)-3-(2-Flu Orophenyl)-1,2,4-Triazolo[4,3-B]Pyridazine], An Agonist Selective For Alpha 2-And Alpha 3-Containing Gaba(A) Receptors, Is A Nonsedating Anxiolytic In Rodents And Primates

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 alpha 1, alpha 2, alpha 3, or alpha 5 subunit but has partial agonist efficacy at the alpha 2 and alpha 3 subtypes and essentially antagonist efficacy at the alpha 1 and alpha 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-beta-carboline-3- carboxamide ( FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel alpha 2/alpha 3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.