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 GABAA 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]
^Carling RW, Madin A, Guiblin A, Russell MG, Moore KW, Mitchinson A, et al. (November 2005). "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. doi:10.1021/jm058034a. PMID16279764.
^Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A, et al. (January 2006). "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. doi:10.1124/jpet.105.089920. PMID16183706. S2CID23047072.
^de Haas SL, de Visser SJ, van der Post JP, de Smet M, Schoemaker RC, Rijnbeek B, et al. (June 2007). "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. doi:10.1177/0269881106072343. PMID17092968. S2CID22626040.
^Polsky-Fisher SL, Vickers S, Cui D, Subramanian R, Arison BH, Agrawal NG, et al. (June 2006). "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. doi:10.1124/dmd.105.008193. PMID16510541. S2CID17373.
^Ma B, Polsky-Fisher SL, Vickers S, Cui D, Rodrigues AD (August 2007). "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. doi:10.1124/dmd.107.014753. PMID17460031. S2CID86847445.
