title: 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 alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates.
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.
authors.affiliation: Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. john_atack@merck.com
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Tye
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: David
authors.initials: D
authors.lastname: Melillo
authors.forename: Linda
authors.initials: L
authors.lastname: Bristow
authors.forename: Fran
authors.initials: F
authors.lastname: Bromidge
authors.forename: Ian
authors.initials: I
authors.lastname: Ragan
authors.forename: Julie
authors.initials: J
authors.lastname: Kerby
authors.forename: Les
authors.initials: L
authors.lastname: Street
authors.forename: Robert
authors.initials: R
authors.lastname: Carling
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: Paul
authors.initials: P
authors.lastname: Whiting
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
mesh_terms: D000161:Acoustic Stimulation; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants / Q000494:pharmacology; D001345:Autoradiography; D003216:Conditioning, Operant / Q000187:drug effects; D003292:Convulsants / Q000494:pharmacology; D004326:Drinking / Q000187:drug effects; D004644:Emotions / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005442:Flumazenil / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D004856:Postural Balance / Q000187:drug effects; D011485:Protein Binding; D011724:Pyridazines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A; D011994:Recombinant Proteins / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012453:Saimiri; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D003292:Convulsants; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; C546258:Gabra3 protein, mouse; C546259:Gabra3 protein, rat; D011724:Pyridazines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D014230:Triazoles; D005442:Flumazenil; D010433:Pentylenetetrazole