TPA-023 explained

TPA-023 (MK-0777) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a mixed, subtype-selective ligand of the benzodiazepine site of α1, α2, α3, and α5-containing GABA_A receptors, where it acts as a partial agonist at benzodiazepine sites of the α2 and α3-containing subtypes, but as a silent antagonist at α1 and α5-containing subtypes.^[1] It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50 times the effective anxiolytic dose.^{[2] [3]}

In human trials on healthy volunteers, TPA-023 was comparable to lorazepam, but lacked negative effects on cognition, memory, alertness or coordination seen with the latter drug.^[4] In Phase II trials, the compound was significantly superior to placebo without inducing sedation. The clinical development was halted due to preclinical toxicity (cataract) in long term dosing studies.^{[5] [6]} TPA-023 is well absorbed following oral administration and extensively metabolised by the liver, with a half-life of 6.7 hours.^[7] The main enzyme involved in its metabolism is CYP3A4, with some contribution by CYP3A5.^[8]

Notes and References

1. Kohut SJ, Ator NA . Novel discriminative stimulus effects of TPA023B, subtype-selective gamma-aminobutyric-acid(A)/benzodiazepine modulator: comparisons with zolpidem, lorazepam, and TPA023 . Pharmacology, Biochemistry, and Behavior . 90 . 1 . 65–73 . July 2008 . 18395780 . 3010402 . 10.1016/j.pbb.2008.02.019 .
2. Carling RW, Madin A, Guiblin A, Russell MG, Moore KW, Mitchinson A, Sohal B, Pike A, Cook SM, Ragan IC, McKernan RM, Quirk K, Ferris P, Marshall G, Thompson SA, Wafford KA, Dawson GR, Atack JR, Harrison T, Castro JL, Street LJ . 6 . 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 gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models . Journal of Medicinal Chemistry . 48 . 23 . 7089–92 . November 2005 . 16279764 . 10.1021/jm058034a .
3. Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, Ragan I, Kerby J, Street L, Carling R, Castro JL, Whiting P, Dawson GR, McKernan RM . 6 . 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 . The Journal of Pharmacology and Experimental Therapeutics . 316 . 1 . 410–22 . January 2006 . 16183706 . 10.1124/jpet.105.089920 . 23047072 .
4. de Haas SL, de Visser SJ, van der Post JP, de Smet M, Schoemaker RC, Rijnbeek B, Cohen AF, Vega JM, Agrawal NG, Goel TV, Simpson RC, Pearson LK, Li S, Hesney M, Murphy MG, van Gerven JM . 6 . Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA(A) alpha(2,3) subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers . Journal of Psychopharmacology . 21 . 4 . 374–83 . June 2007 . 17092968 . 10.1177/0269881106072343 . 22626040 .
5. Möhler H . The rise of a new GABA pharmacology . Neuropharmacology . 60 . 7–8 . 1042–9 . June 2011 . 21035473 . 10.1016/j.neuropharm.2010.10.020 . 46645932 .
6. Atack JR . GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer . CNS Neuroscience & Therapeutics . 14 . 1 . 25–35 . 2008 . 18482097 . 6494020 . 10.1111/j.1527-3458.2007.00034.x .
7. Polsky-Fisher SL, Vickers S, Cui D, Subramanian R, Arison BH, Agrawal NG, Goel TV, Vessey LK, Murphy MG, Lasseter KC, Simpson RC, Vega JM, Rodrigues AD . 6 . Metabolism and disposition of a potent and selective GABA-Aalpha2/3 receptor agonist in healthy male volunteers . Drug Metabolism and Disposition . 34 . 6 . 1004–11 . June 2006 . 16510541 . 10.1124/dmd.105.008193 . 17373 .
8. Ma B, Polsky-Fisher SL, Vickers S, Cui D, Rodrigues AD . Cytochrome P450 3A-dependent metabolism of a potent and selective gamma-aminobutyric acid Aalpha2/3 receptor agonist in vitro: involvement of cytochrome P450 3A5 displaying biphasic kinetics . Drug Metabolism and Disposition . 35 . 8 . 1301–7 . August 2007 . 17460031 . 10.1124/dmd.107.014753 . 86847445 .