TPA-023

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 subtype-selective, mixed agonist-antagonist at GABAA receptors, which acts as a partial agonist at the α2 and α3 subtypes, but as a silent antagonist at α1 and α5 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]

TPA-023
Clinical data
Other namesMK-0777
Routes of
administration		oral
Pharmacokinetic data
Metabolismhepatic
Elimination half-life6.7 hours
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H22FN7O
Molar mass395.442 g·mol−1
3D model (JSmol)
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In human trials on healthy volunteers, TPA-023 was comparable to lorazepam, but had much less side effects on cognition, memory, alertness or coordination.[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]

References
  1. Kohut SJ, Ator NA (July 2008). "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. doi:10.1016/j.pbb.2008.02.019. PMC 3010402. PMID 18395780.
  2. 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. PMID 16279764.
  3. 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. PMID 16183706. S2CID 23047072.
  4. 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. PMID 17092968. S2CID 22626040.
  5. Möhler H (June 2011). "The rise of a new GABA pharmacology". Neuropharmacology. 60 (7–8): 1042–9. doi:10.1016/j.neuropharm.2010.10.020. PMID 21035473. S2CID 46645932.
  6. Atack JR (2008). "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. doi:10.1111/j.1527-3458.2007.00034.x. PMC 6494020. PMID 18482097.
  7. 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. PMID 16510541. S2CID 17373.
  8. 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. PMID 17460031. S2CID 86847445.
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